Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

Author(s): Victoria Lucia Alonso, Luis Emilio Tavernelli, Alejandro Pezza, Pamela Cribb, Carla Ritagliati and Esteban Serra*

Volume 26, Issue 36, 2019

Page: [6544 - 6563] Pages: 20

DOI: 10.2174/0929867325666181031132007

Price: $65

Abstract

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

Keywords: Bromodomains, trypanosoma cruzi, acetylation, bromodomain inhibitors, chagas diseases, drug discovery.

[1]
Clayton, C.; Shapira, M. Post-transcriptional regulation of gene expression in trypanosomes and leishmanias. Mol. Biochem. Parasitol., 2007, 156(2), 93-101.
[http://dx.doi.org/10.1016/j.molbiopara.2007.07.007] [PMID: 17765983]
[2]
Daniels, J-P.; Gull, K.; Wickstead, B. Cell biology of the trypanosome genome. Microbiol. Mol. Biol. Rev., 2010, 74(4), 552-569.
[http://dx.doi.org/10.1128/MMBR.00024-10] [PMID: 21119017]
[3]
Martínez-Calvillo, S.; Vizuet-de-Rueda, J.C.; Florencio-Martínez, L.E.; Manning-Cela, R.G.; Figueroa-Angulo, E.E. Gene expression in trypanosomatid parasites. J. Biomed. Biotechnol., 2010, 2010525241
[http://dx.doi.org/10.1155/2010/525241] [PMID: 20169133]
[4]
Campbell, D.A.; Thomas, S.; Sturm, N.R. Transcription in kinetoplastid protozoa: why be normal? Microbes Infect., 2003, 5(13), 1231-1240.
[http://dx.doi.org/10.1016/j.micinf.2003.09.005] [PMID: 14623019]
[5]
De Gaudenzi, J.G.; Noé, G.; Campo, V.A.; Frasch, A.C.; Cassola, A. Gene expression regulation in trypanosomatids. Essays Biochem., 2011, 51, 31-46.
[http://dx.doi.org/dx.doi: 10.1042/bse0510031] [PMID: 22023440]
[6]
Martínez-Calvillo, S.; Yan, S.; Nguyen, D.; Fox, M.; Stuart, K.; Myler, P.J. Transcription of Leishmania major Friedlin chromosome 1 initiates in both directions within a single region. Mol. Cell, 2003, 11(5), 1291-1299.
[http://dx.doi.org/10.1016/S1097-2765(03)00143-6] [PMID: 12769852]
[7]
Martínez-Calvillo, S.; Nguyen, D.; Stuart, K.; Myler, P.J. Transcription initiation and termination on Leishmania major chromosome 3. Eukaryot. Cell, 2004, 3(2), 506-517.
[http://dx.doi.org/10.1128/EC.3.2.506-517.2004] [PMID: 15075279]
[8]
Narayanan, M.S.; Rudenko, G. TDP1 is an HMG chromatin protein facilitating RNA polymerase I transcription in African trypanosomes. Nucleic Acids Res., 2013, 41(5), 2981-2992.
[http://dx.doi.org/10.1093/nar/gks1469] [PMID: 23361461]
[9]
Povelones, M.L.; Gluenz, E.; Dembek, M.; Gull, K.; Rudenko, G. Histone H1 plays a role in heterochromatin formation and VSG expression site silencing in Trypanosoma brucei. PLoS Pathog., 2012, 8(11)e1003010
[http://dx.doi.org/10.1371/journal.ppat.1003010] [PMID: 23133390]
[10]
Anderson, B.A.; Wong, I.L.K.; Baugh, L.; Ramasamy, G.; Myler, P.J.; Beverley, S.M. Kinetoplastid-specific histone variant functions are conserved in Leishmania major. Mol. Biochem. Parasitol., 2013, 191(2), 53-57.
[http://dx.doi.org/10.1016/j.molbiopara.2013.09.005] [PMID: 24080031]
[11]
Siegel, T.N.; Hekstra, D.R.; Kemp, L.E.; Figueiredo, L.M.; Lowell, J.E.; Fenyo, D.; Wang, X.; Dewell, S.; Cross, G.A. Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei. Genes Dev., 2009, 23(9), 1063-1076.
[http://dx.doi.org/10.1101/gad.1790409] [PMID: 19369410]
[12]
Janzen, C.J.; Fernandez, J.P.; Deng, H.; Diaz, R.; Hake, S.B.; Cross, G.A.M. Unusual histone modifications in Trypanosoma brucei. FEBS Lett., 2006, 580(9), 2306-2310.
[http://dx.doi.org/10.1016/j.febslet.2006.03.044] [PMID: 16580668]
[13]
de Jesus, T.C.L.; Nunes, V.S.; Lopes, M. de C.; Martil, D.E.; Iwai, L.K.; Moretti, N.S.; Machado, F.C.; de Lima-Stein, M.L.; Thiemann, O.H.; Elias, M.C.; Janzen, C.; Schenkman, S.; da Cunha, J.P.C. Chromatin Proteomics Reveals Variable Histone Modifications during the Life Cycle of Trypanosoma cruzi. J. Proteome Res., 2016, 15(6), 2039-2051.
[http://dx.doi.org/10.1021/acs.jproteome.6b00208] [PMID: 27108550]
[14]
Nardelli, S.C.; da Cunha, J.P.C.; Motta, M.C.M.; Schenkman, S. Distinct acetylation of Trypanosoma cruzi histone H4 during cell cycle, parasite differentiation, and after DNA damage. Chromosoma, 2009, 118(4), 487-499.
[http://dx.doi.org/10.1007/s00412-009-0213-9] [PMID: 19396454]
[15]
Schenkman, S.; da Cunha, J.P.C. Response to Horn: Introducing histone modifications in trypanosomes. Trends Parasitol., 2007, 23(6), 242-243.
[http://dx.doi.org/10.1016/j.pt.2007.04.006] [PMID: 17459774]
[16]
Mandava, V.; Fernandez, J.P.; Deng, H.; Janzen, C.J.; Hake, S.B.; Cross, G.A. Histone modifications in Trypanosoma brucei. Mol. Biochem. Parasitol., 2007, 156(1), 41-50.
[http://dx.doi.org/10.1016/j.molbiopara.2007.07.005] [PMID: 17714803]
[17]
Picchi, G.F.A.; Zulkievicz, V.; Krieger, M.A.; Zanchin, N.T.; Goldenberg, S.; de Godoy, L.M.F. Post-translational Modifications of Trypanosoma cruzi Canonical and Variant Histones. J. Proteome Res., 2017, 16(3), 1167-1179.
[http://dx.doi.org/10.1021/acs.jproteome.6b00655] [PMID: 28076955]
[18]
Choi, J.; El-Sayed, N.M. Functional genomics of trypanosomatids. Parasite Immunol., 2012, 34(2-3), 72-79.
[http://dx.doi.org/10.1111/j.1365-3024.2011.01347.x] [PMID: 22132795]
[19]
Respuela, P.; Ferella, M.; Rada-Iglesias, A.; Aslund, L. Histone acetylation and methylation at sites initiating divergent polycistronic transcription in Trypanosoma cruzi. J. Biol. Chem., 2008, 283(23), 15884-15892.
[http://dx.doi.org/10.1074/jbc.M802081200] [PMID: 18400752]
[20]
Thomas, S.; Green, A.; Sturm, N.R.; Campbell, D.A.; Myler, P.J. Histone acetylations mark origins of polycistronic transcription in Leishmania major. BMC Genomics, 2009, 10, 152.
[http://dx.doi.org/10.1186/1471-2164-10-152] [PMID: 19356248]
[21]
Ekanayake, D.; Sabatini, R. Epigenetic regulation of polymerase II transcription initiation in Trypanosoma cruzi: modulation of nucleosome abundance, histone modification, and polymerase occupancy by O-linked thymine DNA glucosylation. Eukaryot. Cell, 2011, 10(11), 1465-1472.
[http://dx.doi.org/10.1128/EC.05185-11] [PMID: 21926332]
[22]
Alonso, V.L.; Serra, E.C. Lysine acetylation: elucidating the components of an emerging global signaling pathway in trypanosomes. J. Biomed. Biotechnol., 2012, 2012452934
[http://dx.doi.org/10.1155/2012/452934] [PMID: 23093844]
[23]
Miao, J.; Lawrence, M.; Jeffers, V.; Zhao, F.; Parker, D.; Ge, Y.; Sullivan, W.J. Jr.; Cui, L. Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. Mol. Microbiol., 2013, 89(4), 660-675.
[http://dx.doi.org/10.1111/mmi.12303] [PMID: 23796209]
[24]
Jeffers, V.; Sullivan, W.J. Jr Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii. Eukaryot. Cell, 2012, 11(6), 735-742.
[http://dx.doi.org/10.1128/EC.00088-12] [PMID: 22544907]
[25]
Moretti, N.S.; Cestari, I.; Anupama, A.; Stuart, K.; Schenkman, S. Comparative proteomic analysis of lysine acetylation in trypanosomes. J. Proteome Res., 2018, 17(1), 374-385.
[http://dx.doi.org/10.1021/acs.jproteome.7b00603] [PMID: 29168382]
[26]
Souza, Wd. Structural organization of Trypanosoma cruzi. Mem. Inst. Oswaldo Cruz, 2009, 104(Suppl. 1), 89-100.
[http://dx.doi.org/10.1590/S0074-02762009000900014] [PMID: 19753463]
[27]
Souto-Padron, T.; Cunha e Silva, N.L.; de Souza, W. Acetylated alpha-tubulin in Trypanosoma cruzi: immunocytochemical localization. Mem. Inst. Oswaldo Cruz, 1993, 88(4), 517-528.
[http://dx.doi.org/10.1590/S0074-02761993000400004] [PMID: 8139463]
[28]
Schneider, A.; Sherwin, T.; Sasse, R.; Russell, D.G.; Gull, K.; Seebeck, T. Subpellicular and flagellar microtubules of Trypanosoma brucei brucei contain the same alpha-tubulin isoforms. J. Cell Biol., 1987, 104(3), 431-438.
[http://dx.doi.org/10.1083/jcb.104.3.431] [PMID: 3818788]
[29]
Opperdoes, F.R. Compartmentation of carbohydrate metabolism in trypanosomes. Annu. Rev. Microbiol., 1987, 41, 127-151.
[http://dx.doi.org/10.1146/annurev.mi.41.100187.001015] [PMID: 3120638]
[30]
Michels, P.A.; Hannaert, V.; Bringaud, F. Metabolic aspects of glycosomes in trypanosomatidae - new data and views, 16th ed; Parasitol. Today Pers, 2000, pp. 482-489.
[31]
Ritagliati, C.; Villanova, G.V.; Alonso, V.L.; Zuma, A.A.; Cribb, P.; Motta, M.C.M.; Serra, E.C. Glycosomal bromodomain factor 1 from Trypanosoma cruzi enhances trypomastigote cell infection and intracellular amastigote growth. Biochem. J., 2016, 473(1), 73-85.
[http://dx.doi.org/10.1042/BJ20150986] [PMID: 26500280]
[32]
Tamkun, J.W.; Deuring, R.; Scott, M.P.; Kissinger, M.; Pattatucci, A.M.; Kaufman, T.C.; Kennison, J.A. brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2. Cell, 1992, 68(3), 561-572.
[http://dx.doi.org/10.1016/0092-8674(92)90191-E] [PMID: 1346755]
[33]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[34]
Dhalluin, C.; Carlson, J.E.; Zeng, L.; He, C.; Aggarwal, A.K.; Zhou, M.M. Structure and ligand of a histone acetyltransferase bromodomain. Nature, 1999, 399(6735), 491-496.
[http://dx.doi.org/10.1038/20974] [PMID: 10365964]
[35]
Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O. Sachchidanand; Sanchez, R.; Zeleznik-Le, N.J.; Ronai, Z.; Zhou, M.M. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol. Cell, 2004, 13(2), 251-263.
[http://dx.doi.org/10.1016/S1097-2765(03)00528-8] [PMID: 14759370]
[36]
Zeng, L.; Zhang, Q.; Gerona-Navarro, G.; Moshkina, N.; Zhou, M-M. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300. Structure, 2008, 16(4), 643-652.
[http://dx.doi.org/10.1016/j.str.2008.01.010] [PMID: 18400184]
[37]
Plotnikov, A.N.; Yang, S.; Zhou, T.J.; Rusinova, E.; Frasca, A.; Zhou, M-M. Structural insights into acetylated-histone H4 recognition by the bromodomain-PHD finger module of human transcriptional coactivator CBP. Structure, 2014, 22(2), 353-360.
[http://dx.doi.org/10.1016/j.str.2013.10.021] [PMID: 24361270]
[38]
Filippakopoulos, P.; Picaud, S.; Mangos, M.; Keates, T.; Lambert, J-P.; Barsyte-Lovejoy, D.; Felletar, I.; Volkmer, R.; Müller, S.; Pawson, T.; Gingras, A-C.; Arrowsmith, C.H.; Knapp, S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell, 2012, 149(1), 214-231.
[http://dx.doi.org/10.1016/j.cell.2012.02.013] [PMID: 22464331]
[39]
Gamsjaeger, R.; Webb, S.R.; Lamonica, J.M.; Billin, A.; Blobel, G.A.; Mackay, J.P. Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3. Mol. Cell. Biol., 2011, 31(13), 2632-2640.
[http://dx.doi.org/10.1128/MCB.05413-11] [PMID: 21555453]
[40]
Filippakopoulos, P.; Picaud, S.; Fedorov, O.; Keller, M.; Wrobel, M.; Morgenstern, O.; Bracher, F.; Knapp, S. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem., 2012, 20(6), 1878-1886.
[http://dx.doi.org/10.1016/j.bmc.2011.10.080] [PMID: 22137933]
[41]
Charlop-Powers, Z.; Zeng, L.; Zhang, Q.; Zhou, M-M. Structural insights into selective histone H3 recognition by the human Polybromo bromodomain 2. Cell Res., 2010, 20(5), 529-538.
[http://dx.doi.org/10.1038/cr.2010.43] [PMID: 20368734]
[42]
Umehara, T.; Nakamura, Y.; Jang, M.K.; Nakano, K.; Tanaka, A.; Ozato, K.; Padmanabhan, B.; Yokoyama, S. Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain. J. Biol. Chem., 2010, 285(10), 7610-7618.
[http://dx.doi.org/10.1074/jbc.M109.062422] [PMID: 20048151]
[43]
Owen, D.J.; Ornaghi, P.; Yang, J.C.; Lowe, N.; Evans, P.R.; Ballario, P.; Neuhaus, D.; Filetici, P.; Travers, A.A. The structural basis for the recognition of acetylated histone H4 by the bromodomain of histone acetyltransferase gcn5p. EMBO J., 2000, 19(22), 6141-6149.
[http://dx.doi.org/10.1093/emboj/19.22.6141] [PMID: 11080160]
[44]
Sanchez, R.; Meslamani, J.; Zhou, M-M. The bromodomain: from epigenome reader to druggable target. Biochim. Biophys. Acta, 2014, 1839(8), 676-685.
[http://dx.doi.org/10.1016/j.bbagrm.2014.03.011] [PMID: 24686119]
[45]
Sanchez, R.; Zhou, M-M. The role of human bromodomains in chromatin biology and gene transcription. Curr. Opin. Drug Discov. Devel., 2009, 12(5), 659-665.
[PMID: 19736624]
[46]
Finn, R.D.; Coggill, P.; Eberhardt, R.Y.; Eddy, S.R.; Mistry, J.; Mitchell, A.L.; Potter, S.C.; Punta, M.; Qureshi, M.; Sangrador-Vegas, A.; Salazar, G.A.; Tate, J.; Bateman, A. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res., 2016, 44(D1), D279-D285.
[http://dx.doi.org/10.1093/nar/gkv1344] [PMID: 26673716]
[47]
Jenuwein, T.; Allis, C.D. Translating the histone code. Science, 2001, 293(5532), 1074-1080.
[http://dx.doi.org/10.1126/science.1063127] [PMID: 11498575]
[48]
Fujisawa, T.; Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol., 2017, 18(4), 246-262.
[http://dx.doi.org/10.1038/nrm.2016.143] [PMID: 28053347]
[49]
Delcuratolo, M.; Fertey, J.; Schneider, M.; Schuetz, J.; Leiprecht, N.; Hudjetz, B.; Brodbeck, S.; Corall, S.; Dreer, M.; Schwab, R.M.; Grimm, M.; Wu, S-Y.; Stubenrauch, F.; Chiang, C-M.; Iftner, T. Papillomavirus-associated tumor formation critically depends on c-fos expression induced by viral protein E2 and bromodomain protein Brd4. PLoS Pathog., 2016, 12(1)e1005366
[http://dx.doi.org/10.1371/journal.ppat.1005366] [PMID: 26727473]
[50]
Crowley, T.; Brunori, M.; Rhee, K.; Wang, X.; Wolgemuth, D.J. Change in nuclear-cytoplasmic localization of a double-bromodomain protein during proliferation and differentiation of mouse spinal cord and dorsal root ganglia. Brain Res. Dev. Brain Res., 2004, 149(2), 93-101.
[http://dx.doi.org/10.1016/j.devbrainres.2003.12.011] [PMID: 15063089]
[51]
Trousdale, R.K.; Wolgemuth, D.J. Bromodomain containing 2 (Brd2) is expressed in distinct patterns during ovarian folliculogenesis independent of FSH or GDF9 action. Mol. Reprod. Dev., 2004, 68(3), 261-268.
[http://dx.doi.org/10.1002/mrd.20059] [PMID: 15112318]
[52]
Liu, H.; Li, X.; Niu, Z.; Zhang, L.; Zhou, M.; Huang, H.; He, J.; Zhang, W.; Xiao, L.; Tang, Y.; Wang, L.; Li, G. Preparation of polyclonal antibody specific for BRD7 and detection of its expression pattern in the human fetus. J. Histochem. Cytochem., 2008, 56(6), 531-538.
[http://dx.doi.org/10.1369/jhc.7A7340.2007] [PMID: 18071067]
[53]
Ullah, M.; Pelletier, N.; Xiao, L.; Zhao, S.P.; Wang, K.; Degerny, C.; Tahmasebi, S.; Cayrou, C.; Doyon, Y.; Goh, S-L.; Champagne, N.; Côté, J.; Yang, X-J. Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Mol. Cell. Biol., 2008, 28(22), 6828-6843.
[http://dx.doi.org/10.1128/MCB.01297-08] [PMID: 18794358]
[54]
Zong, R.T.; Das, C.; Tucker, P.W. Regulation of matrix attachment region-dependent, lymphocyte-restricted transcription through differential localization within promyelocytic leukemia nuclear bodies. EMBO J., 2000, 19(15), 4123-4133.
[http://dx.doi.org/10.1093/emboj/19.15.4123] [PMID: 10921892]
[55]
Chang, P.; Fan, X.; Chen, J. Function and subcellular localization of Gcn5, a histone acetyltransferase in Candida albicans. Fungal Genet. Biol., 2015, 81, 132-141.
[http://dx.doi.org/10.1016/j.fgb.2015.01.011] [PMID: 25656079]
[56]
Tamura, K.; Peterson, D.; Peterson, N.; Stecher, G.; Nei, M.; Kumar, S. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol., 2011, 28(10), 2731-2739.
[http://dx.doi.org/10.1093/molbev/msr121] [PMID: 21546353]
[57]
Alonso, V.L.; Villanova, G.V.; Ritagliati, C.; Machado Motta, M.C.; Cribb, P.; Serra, E.C. Trypanosoma cruzi bromodomain factor 3 binds acetylated α-tubulin and concentrates in the flagellum during metacyclogenesis. Eukaryot. Cell, 2014, 13(6), 822-831.
[http://dx.doi.org/10.1128/EC.00341-13] [PMID: 24747213]
[58]
Villanova, G.V.; Nardelli, S.C.; Cribb, P.; Magdaleno, A.; Silber, A.M.; Motta, M.C.M.; Schenkman, S.; Serra, E. Trypanosoma cruzi bromodomain factor 2 (BDF2) binds to acetylated histones and is accumulated after UV irradiation. Int. J. Parasitol., 2009, 39(6), 665-673.
[http://dx.doi.org/10.1016/j.ijpara.2008.11.013] [PMID: 19136002]
[59]
Alonso, V.L.; Ritagliati, C.; Cribb, P.; Cricco, J.A.; Serra, E.C. Overexpression of bromodomain factor 3 in Trypanosoma cruzi (TcBDF3) affects differentiation of the parasite and protects it against bromodomain inhibitors. FEBS J., 2016, 283(11), 2051-2066.
[http://dx.doi.org/10.1111/febs.13719] [PMID: 27007774]
[60]
Milagros, Camara. Mde.L.; Bouvier, L.A.; Miranda, M.R.; Pereira, C.A. Identification and validation of Trypanosoma cruzi’s glycosomal adenylate kinase containing a peroxisomal targeting signal. Exp. Parasitol., 2012, 130(4), 408-411.
[http://dx.doi.org/10.1016/j.exppara.2012.01.020] [PMID: 22343032]
[61]
Haanstra, J.R.; González-Marcano, E.B.; Gualdrón-López, M.; Michels, P.A.M. Biogenesis, maintenance and dynamics of glycosomes in trypanosomatid parasites. Biochim. Biophys. Acta, 2016, 1863(5), 1038-1048.
[http://dx.doi.org/10.1016/j.bbamcr.2015.09.015] [PMID: 26384872]
[62]
Zhao, S.; Xu, W.; Jiang, W.; Yu, W.; Lin, Y.; Zhang, T.; Yao, J.; Zhou, L.; Zeng, Y.; Li, H.; Li, Y.; Shi, J.; An, W.; Hancock, S.M.; He, F.; Qin, L.; Chin, J.; Yang, P.; Chen, X.; Lei, Q.; Xiong, Y.; Guan, K-L. Regulation of cellular metabolism by protein lysine acetylation. Science, 2010, 327(5968), 1000-1004.
[http://dx.doi.org/10.1126/science.1179689] [PMID: 20167786]
[63]
Horn, P.J.; Peterson, C.L. The bromodomain: a regulator of ATP-dependent chromatin remodeling? Front. Biosci., 2001, 6, D1019-D1023.
[http://dx.doi.org/10.2741/Horn] [PMID: 11487477]
[64]
Yang, X.; Wu, X.; Zhang, J.; Zhang, X.; Xu, C.; Liao, S.; Tu, X. Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2 from Trypanosoma brucei. Biochem. J., 2017, 474(22), 3817-3830.
[http://dx.doi.org/10.1042/BCJ20170619] [PMID: 29025975]
[65]
Schulz, D.; Mugnier, M.R.; Paulsen, E.M.; Kim, H.S.; Chung, C.W.; Tough, D.F.; Rioja, I.; Prinjha, R.K.; Papavasiliou, F.N.; Debler, E.W. Bromodomain proteins contribute to maintenance of bloodstream form stage identity in the African Trypanosome. PLoS Biol., 2015, 13(12)e1002316
[http://dx.doi.org/10.1371/journal.pbio.1002316] [PMID: 26646171]
[66]
Alsford, S.; Horn, D. Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1A and CAF-1b in Trypanosoma brucei. Nucleic Acids Res., 2012, 40(20), 10150-10160.
[http://dx.doi.org/10.1093/nar/gks813] [PMID: 22941664]
[67]
Kaida, D.; Motoyoshi, H.; Tashiro, E.; Nojima, T.; Hagiwara, M.; Ishigami, K.; Watanabe, H.; Kitahara, T.; Yoshida, T.; Nakajima, H.; Tani, T.; Horinouchi, S.; Yoshida, M. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol., 2007, 3(9), 576-583.
[http://dx.doi.org/10.1038/nchembio.2007.18] [PMID: 17643111]
[68]
Kotake, Y.; Sagane, K.; Owa, T.; Mimori-Kiyosue, Y.; Shimizu, H.; Uesugi, M.; Ishihama, Y.; Iwata, M.; Mizui, Y. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat. Chem. Biol., 2007, 3(9), 570-575.
[http://dx.doi.org/10.1038/nchembio.2007.16] [PMID: 17643112]
[69]
Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M.R.; Wang, Y.; Christie, A.L.; West, N.; Cameron, M.J.; Schwartz, B.; Heightman, T.D.; La Thangue, N.; French, C.A.; Wiest, O.; Kung, A.L.; Knapp, S.; Bradner, J.E. Selective inhibition of BET bromodomains. Nature, 2010, 468(7327), 1067-1073.
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
[70]
Chung, C-W.; Coste, H.; White, J.H.; Mirguet, O.; Wilde, J.; Gosmini, R.L.; Delves, C.; Magny, S.M.; Woodward, R.; Hughes, S.A.; Boursier, E.V.; Flynn, H.; Bouillot, A.M.; Bamborough, P.; Brusq, J-M.G.; Gellibert, F.J.; Jones, E.J.; Riou, A.M.; Homes, P.; Martin, S.L.; Uings, I.J.; Toum, J.; Clement, C.A.; Boullay, A-B.; Grimley, R.L.; Blandel, F.M.; Prinjha, R.K.; Lee, K.; Kirilovsky, J.; Nicodeme, E. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem., 2011, 54(11), 3827-3838.
[http://dx.doi.org/10.1021/jm200108t] [PMID: 21568322]
[71]
Dawson, M.A.; Prinjha, R.K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W-I.; Robson, S.C.; Chung, C.W.; Hopf, C.; Savitski, M.M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T.D.; Roberts, E.J.; Soden, P.E.; Auger, K.R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A.K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B.J.P.; Kouzarides, T. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 2011, 478(7370), 529-533.
[http://dx.doi.org/10.1038/nature10509] [PMID: 21964340]
[72]
Chung, C.W.; Witherington, J. Progress in the discovery of small-molecule inhibitors of bromodomain--histone interactions. J. Biomol. Screen., 2011, 16(10), 1170-1185.
[http://dx.doi.org/10.1177/1087057111421372] [PMID: 21956175]
[73]
Borah, J.C.; Mujtaba, S.; Karakikes, I.; Zeng, L.; Muller, M.; Patel, J.; Moshkina, N.; Morohashi, K.; Zhang, W.; Gerona-Navarro, G.; Hajjar, R.J.; Zhou, M-M. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol., 2011, 18(4), 531-541.
[http://dx.doi.org/10.1016/j.chembiol.2010.12.021] [PMID: 21513889]
[74]
Shuker, S.B.; Hajduk, P.J.; Meadows, R.P.; Fesik, S.W. Discovering high-affinity ligands for proteins: SAR by NMR. Science, 1996, 274(5292), 1531-1534.
[http://dx.doi.org/10.1126/science.274.5292.1531] [PMID: 8929414]
[75]
Neumann, T.; Junker, H-D.; Schmidt, K.; Sekul, R. SPR-based fragment screening: advantages and applications. Curr. Top. Med. Chem., 2007, 7(16), 1630-1642.
[http://dx.doi.org/10.2174/156802607782341073] [PMID: 17979772]
[76]
Niesen, F.H.; Berglund, H.; Vedadi, M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc., 2007, 2(9), 2212-2221.
[http://dx.doi.org/10.1038/nprot.2007.321] [PMID: 17853878]
[77]
Fedorov, O.; Marsden, B.; Pogacic, V.; Rellos, P.; Müller, S.; Bullock, A.N.; Schwaller, J.; Sundström, M.; Knapp, S. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl. Acad. Sci. USA, 2007, 104(51), 20523-20528.
[http://dx.doi.org/10.1073/pnas.0708800104] [PMID: 18077363]
[78]
Nicodeme, E.; Jeffrey, K.L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C-W.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; White, J.; Kirilovsky, J.; Rice, C.M.; Lora, J.M.; Prinjha, R.K.; Lee, K.; Tarakhovsky, A. Suppression of inflammation by a synthetic histone mimic. Nature, 2010, 468(7327), 1119-1123.
[http://dx.doi.org/10.1038/nature09589] [PMID: 21068722]
[79]
Philpott, M.; Yang, J.; Tumber, T.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Keates, T.; Felletar, I.; Ciulli, A.; Knapp, S.; Heightman, T.D. Bromodomain-peptide displacement assays for interactome mapping and inhibitor discovery. Mol. Biosyst., 2011, 7(10), 2899-2908.
[http://dx.doi.org/10.1039/c1mb05099k] [PMID: 21804994]
[80]
Chen, Z.; Zhang, H.; Liu, S.; Xie, Y.; Jiang, H.; Lu, W.; Xu, H.; Yue, L.; Zhang, Y.; Ding, H.; Zheng, M.; Yu, K.; Chen, K.; Jiang, H.; Luo, C. Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay. MedChemComm, 2017, 8(6), 1322-1331.
[http://dx.doi.org/10.1039/C7MD00083A] [PMID: 30108844]
[81]
Garnier, J-M.; Sharp, P.P.; Burns, C.J. BET bromodomain inhibitors: A patent review. Expert Opin. Ther. Pat., 2014, 24(2), 185-199.
[http://dx.doi.org/10.1517/13543776.2014.859244] [PMID: 24261714]
[82]
Bamborough, P.; Diallo, H.; Goodacre, J.D.; Gordon, L.; Lewis, A.; Seal, J.T.; Wilson, D.M.; Woodrow, M.D.; Chung, C.W. Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J. Med. Chem., 2012, 55(2), 587-596.
[http://dx.doi.org/10.1021/jm201283q] [PMID: 22136469]
[83]
Gerona-Navarro, G. Yoel-Rodríguez; Mujtaba, S.; Frasca, A.; Patel, J.; Zeng, L.; Plotnikov, A.N.; Osman, R.; Zhou, M.M. Rational design of cyclic peptide modulators of the transcriptional coactivator CBP: a new class of p53 inhibitors. J. Am. Chem. Soc., 2011, 133(7), 2040-2043.
[http://dx.doi.org/10.1021/ja107761h] [PMID: 21271695]
[84]
Hu, P.; Wang, X.; Zhang, B.; Zhang, S.; Wang, Q.; Wang, Z. Fluorescence polarization for the evaluation of small-molecule inhibitors of PCAF BRD/Tat-AcK50 association. ChemMedChem, 2014, 9(5), 928-931.
[http://dx.doi.org/10.1002/cmdc.201300499] [PMID: 24474698]
[85]
Alonso, V.L.; Ritagliati, C.; Cribb, P.; Cricco, J.; Serra, E. Overexpression of bromodomain factor 3 in Trypanosoma cruzi (TcBDF3) affects parasite differentiation and protects it against bromodomain inhibitors. FEBS J., 2016, 283(11), 2051-2066.
[http://dx.doi.org/10.1111/febs.13719] [PMID: 27007774]
[86]
Ramallo, I.A.; Alonso, V.L.; Rua, F.; Serra, E.; Furlan, R.L.E. A bioactive Trypanosoma cruzi Bromodomain inhibitor from chemically engineered extracts. ACS Comb. Sci., 2018, 20(4), 220-228.
[http://dx.doi.org/10.1021/acscombsci.7b00172] [PMID: 29481050]
[87]
García, P.; Alonso, V.L.; Serra, E.; Escalante, A.M.; Furlan, R.L.E. Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry. ACS Med. Chem. Lett., 2018, 9(10), 1002-1006.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00247] [PMID: 30344907]
[88]
Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V-L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A-B.; Boursier, E.; Martin, S.; Brusq, J-M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151. Bioorg. Med. Chem. Lett., 2012, 22(8), 2963-2967.
[http://dx.doi.org/10.1016/j.bmcl.2012.01.125] [PMID: 22386529]
[89]
Ito, T.; Umehara, T.; Sasaki, K.; Nakamura, Y.; Nishino, N.; Terada, T.; Shirouzu, M.; Padmanabhan, B.; Yokoyama, S.; Ito, A.; Yoshida, M. Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem. Biol., 2011, 18(4), 495-507.
[http://dx.doi.org/10.1016/j.chembiol.2011.02.009] [PMID: 21513886]
[90]
Philpott, M.; Rogers, C.M.; Yapp, C.; Wells, C.; Lambert, J-P.; Strain-Damerell, C.; Burgess-Brown, N.A.; Gingras, A-C.; Knapp, S.; Müller, S. Assessing cellular efficacy of bromodomain inhibitors using fluorescence recovery after photobleaching. Epigenetics Chromatin, 2014, 7, 14.
[http://dx.doi.org/10.1186/1756-8935-7-14] [PMID: 25097667]
[91]
Meslamani, J.; Smith, S.G.; Sanchez, R.; Zhou, M-M. ChEpiMod: a knowledgebase for chemical modulators of epigenome reader domains. Bioinformatics, 2014, 30(10), 1481-1483.
[http://dx.doi.org/10.1093/bioinformatics/btu052] [PMID: 24470572]
[92]
Hewings, D.S.; Rooney, T.P.C.; Jennings, L.E.; Hay, D.A.; Schofield, C.J.; Brennan, P.E.; Knapp, S.; Conway, S.J. Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions. J. Med. Chem., 2012, 55(22), 9393-9413.
[http://dx.doi.org/10.1021/jm300915b] [PMID: 22924434]
[93]
Brand, M.; Measures, A.R.; Wilson, B.G.; Cortopassi, W.A.; Alexander, R.; Höss, M.; Hewings, D.S.; Rooney, T.P.C.; Paton, R.S.; Conway, S.J. Small molecule inhibitors of bromodomain-acetyl-lysine interactions. ACS Chem. Biol., 2015, 10(1), 22-39.
[http://dx.doi.org/10.1021/cb500996u] [PMID: 25549280]
[94]
Theodoulou, N.H.; Tomkinson, N.C.; Prinjha, R.K.; Humphreys, P.G. Clinical progress and pharmacology of small molecule bromodomain inhibitors. Curr. Opin. Chem. Biol., 2016, 33, 58-66.
[http://dx.doi.org/10.1016/j.cbpa.2016.05.028] [PMID: 27295577]
[95]
Mirguet, O.; Gosmini, R.; Toum, J.; Clément, C.A.; Barnathan, M.; Brusq, J-M.; Mordaunt, J.E.; Grimes, R.M.; Crowe, M.; Pineau, O.; Ajakane, M.; Daugan, A.; Jeffrey, P.; Cutler, L.; Haynes, A.C.; Smithers, N.N.; Chung, C.W.; Bamborough, P.; Uings, I.J.; Lewis, A.; Witherington, J.; Parr, N.; Prinjha, R.K.; Nicodème, E. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem., 2013, 56(19), 7501-7515.
[http://dx.doi.org/10.1021/jm401088k] [PMID: 24015967]
[96]
Gosmini, R.; Nguyen, V.L.; Toum, J.; Simon, C.; Brusq, J-M.G.; Krysa, G.; Mirguet, O.; Riou-Eymard, A.M.; Boursier, E.V.; Trottet, L.; Bamborough, P.; Clark, H.; Chung, C.W.; Cutler, L.; Demont, E.H.; Kaur, R.; Lewis, A.J.; Schilling, M.B.; Soden, P.E.; Taylor, S.; Walker, A.L.; Walker, M.D.; Prinjha, R.K.; Nicodème, E. The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J. Med. Chem., 2014, 57(19), 8111-8131.
[http://dx.doi.org/10.1021/jm5010539] [PMID: 25249180]
[97]
Coudé, M-M.; Braun, T.; Berrou, J.; Dupont, M.; Bertrand, S.; Masse, A.; Raffoux, E.; Itzykson, R.; Delord, M.; Riveiro, M.E.; Herait, P.; Baruchel, A.; Dombret, H.; Gardin, C. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget, 2015, 6(19), 17698-17712.
[http://dx.doi.org/10.18632/oncotarget.4131] [PMID: 25989842]
[98]
Wong, C.; Laddha, S.V.; Tang, L.; Vosburgh, E.; Levine, A.J.; Normant, E.; Sandy, P.; Harris, C.R.; Chan, C.S.; Xu, E.Y. The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors. Cell Death Dis., 2014, 5e1450
[http://dx.doi.org/10.1038/cddis.2014.396] [PMID: 25299775]
[99]
Zhao, Y.; Yang, C-Y.; Wang, S. The making of I-BET762, a BET bromodomain inhibitor now in clinical development. J. Med. Chem., 2013, 56(19), 7498-7500.
[http://dx.doi.org/10.1021/jm4014407] [PMID: 24107192]
[100]
Asangani, I.A.; Wilder-Romans, K.; Dommeti, V.L.; Krishnamurthy, P.M.; Apel, I.J.; Escara-Wilke, J.; Plymate, S.R.; Navone, N.M.; Wang, S.; Feng, F.Y.; Chinnaiyan, A.M. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol. Cancer Res., 2016, 14(4), 324-331.
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0472] [PMID: 26792867]
[101]
Berenguer-Daizé, C.; Astorgues-Xerri, L.; Odore, E.; Cayol, M.; Cvitkovic, E.; Noel, K.; Bekradda, M.; MacKenzie, S.; Rezai, K.; Lokiec, F.; Riveiro, M.E.; Ouafik, L. OTX015 (MK-8628), a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone and in combination with conventional therapies in glioblastoma models. Int. J. Cancer, 2016, 139(9), 2047-2055.
[http://dx.doi.org/10.1002/ijc.30256] [PMID: 27388964]
[102]
Odore, E.; Lokiec, F.; Cvitkovic, E.; Bekradda, M.; Herait, P.; Bourdel, F.; Kahatt, C.; Raffoux, E.; Stathis, A.; Thieblemont, C.; Quesnel, B.; Cunningham, D.; Riveiro, M.E.; Rezaï, K.; Phase, I. Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor otx015 in patients with haematologic malignancies. Clin. Pharmacokinet., 2016, 55(3), 397-405.
[http://dx.doi.org/10.1007/s40262-015-0327-6] [PMID: 26341814]
[103]
Moros, A.; Rodríguez, V.; Saborit-Villarroya, I.; Montraveta, A.; Balsas, P.; Sandy, P.; Martínez, A.; Wiestner, A.; Normant, E.; Campo, E.; Pérez-Galán, P.; Colomer, D.; Roué, G. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma. Leukemia, 2014, 28(10), 2049-2059.
[http://dx.doi.org/10.1038/leu.2014.106] [PMID: 24721791]
[104]
King, B.; Trimarchi, T.; Reavie, L.; Xu, L.; Mullenders, J.; Ntziachristos, P.; Aranda-Orgilles, B.; Perez-Garcia, A.; Shi, J.; Vakoc, C.; Sandy, P.; Shen, S.S.; Ferrando, A.; Aifantis, I. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell, 2013, 153(7), 1552-1566.
[http://dx.doi.org/10.1016/j.cell.2013.05.041] [PMID: 23791182]
[105]
Hay, D.A.; Fedorov, O.; Martin, S.; Singleton, D.C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O.P.; Rogers, C.M.; Conway, S.J.; Rooney, T.P.C.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M.E.; Müller, S.; Knapp, S.; Schofield, C.J.; Brennan, P.E. Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains. J. Am. Chem. Soc., 2014, 136(26), 9308-9319.
[http://dx.doi.org/10.1021/ja412434f] [PMID: 24946055]
[106]
Hammitzsch, A.; Tallant, C.; Fedorov, O.; O’Mahony, A.; Brennan, P.E.; Hay, D.A.; Martinez, F.O.; Al-Mossawi, M.H.; de Wit, J.; Vecellio, M.; Wells, C.; Wordsworth, P.; Müller, S.; Knapp, S.; Bowness, P. CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses. Proc. Natl. Acad. Sci. USA, 2015, 112(34), 10768-10773.
[http://dx.doi.org/10.1073/pnas.1501956112] [PMID: 26261308]
[107]
Seal, J.; Lamotte, Y.; Donche, F.; Bouillot, A.; Mirguet, O.; Gellibert, F.; Nicodeme, E.; Krysa, G.; Kirilovsky, J.; Beinke, S.; McCleary, S.; Rioja, I.; Bamborough, P.; Chung, C-W.; Gordon, L.; Lewis, T.; Walker, A.L.; Cutler, L.; Lugo, D.; Wilson, D.M.; Witherington, J.; Lee, K.; Prinjha, R.K. Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A). Bioorg. Med. Chem. Lett., 2012, 22(8), 2968-2972.
[http://dx.doi.org/10.1016/j.bmcl.2012.02.041] [PMID: 22437115]
[108]
Puissant, A.; Frumm, S.M.; Alexe, G.; Bassil, C.F.; Qi, J.; Chanthery, Y.H.; Nekritz, E.A.; Zeid, R.; Gustafson, W.C.; Greninger, P.; Garnett, M.J.; McDermott, U.; Benes, C.H.; Kung, A.L.; Weiss, W.A.; Bradner, J.E.; Stegmaier, K. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov., 2013, 3(3), 308-323.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0418] [PMID: 23430699]
[109]
Xiao, Y.; Shanghui, L.; Xiaoming, T. https://www.google.com/patents/CN107308167A?cl=en Trypanosoma brucei compounds can kill its application in the treatment of trypanosomiasis
[110]
Jeffers, V.; Kamau, E.T.; Srinivasan, A.R.; Harper, J.; Sankaran, P.; Post, S.E.; Varberg, J.M.; Sullivan, W.J., Jr; Boyle, J.P. TgPRELID, a mitochondrial protein linked to multidrug resistance in the parasite. Toxoplasma gondii. MSphere, 2017, 2(1), e00229-e16.
[http://dx.doi.org/10.1128/mSphere.00229-16] [PMID: 28168222]
[111]
Bailey, D.; Jahagirdar, R.; Gordon, A.; Hafiane, A.; Campbell, S.; Chatur, S.; Wagner, G.S.; Hansen, H.C.; Chiacchia, F.S.; Johansson, J.; Krimbou, L.; Wong, N.C.W.; Genest, J. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J. Am. Coll. Cardiol., 2010, 55(23), 2580-2589.
[http://dx.doi.org/10.1016/j.jacc.2010.02.035] [PMID: 20513599]
[112]
Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; Fedorov, O.; Müller, S.; Brennan, P.E.; Knapp, S.; Filippakopoulos, P. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA, 2013, 110(49), 19754-19759.
[http://dx.doi.org/10.1073/pnas.1310658110] [PMID: 24248379]
[113]
Fish, P.V.; Filippakopoulos, P.; Bish, G.; Brennan, P.E.; Bunnage, M.E.; Cook, A.S.; Federov, O.; Gerstenberger, B.S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D.R.; Philpott, M.; Picaud, S.; Primiano, M.J.; Ralph, M.J.; Sciammetta, N.; Trzupek, J.D. Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. J. Med. Chem., 2012, 55(22), 9831-9837.
[http://dx.doi.org/10.1021/jm3010515] [PMID: 23095041]
[114]
Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P.V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M.E.; Owen, D.R.; Bradner, J.E.; Taniere, P.; O’Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res., 2013, 73(11), 3336-3346.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3292] [PMID: 23576556]
[115]
Chen, P.; Chaikuad, A.; Bamborough, P.; Bantscheff, M.; Bountra, C.; Chung, C-W.; Fedorov, O.; Grandi, P.; Jung, D.; Lesniak, R.; Lindon, M.; Müller, S.; Philpott, M.; Prinjha, R.; Rogers, C.; Selenski, C.; Tallant, C.; Werner, T.; Willson, T.M.; Knapp, S.; Drewry, D.H. Discovery and characterization of GSK2801, a selective chemical probe for the bromodomains BAZ2A and BAZ2B. J. Med. Chem., 2016, 59(4), 1410-1424.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00209] [PMID: 25799074]
[116]
Picaud, S.; Leonards, K.; Lambert, J-P.; Dovey, O.; Wells, C.; Fedorov, O.; Monteiro, O.; Fujisawa, T.; Wang, C-Y.; Lingard, H.; Tallant, C.; Nikbin, N.; Guetzoyan, L.; Ingham, R.; Ley, S.V.; Brennan, P.; Muller, S.; Samsonova, A.; Gingras, A-C.; Schwaller, J.; Vassiliou, G.; Knapp, S.; Filippakopoulos, P. Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia. Sci. Adv., 2016, 2(10)e1600760
[http://dx.doi.org/10.1126/sciadv.1600760] [PMID: 27757418]
[117]
Fedorov, O.; Lingard, H.; Wells, C.; Monteiro, O.P.; Picaud, S.; Keates, T.; Yapp, C.; Philpott, M.; Martin, S.J.; Felletar, I.; Marsden, B.D.; Filippakopoulos, P.; Müller, S.; Knapp, S.; Brennan, P.E. [1,2,4]triazolo[4,3-a]phthalazines: inhibitors of diverse bromodomains. J. Med. Chem., 2014, 57(2), 462-476.
[http://dx.doi.org/10.1021/jm401568s] [PMID: 24313754]
[118]
Pan, H.; Lu, P.; Shen, Y.; Wang, Y.; Jiang, Z.; Yang, X.; Zhong, Y.; Yang, H.; Khan, I.U.; Zhou, M.; Li, B.; Zhang, Z.; Xu, J.; Lu, H.; Zhu, H. The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells. Oncotarget, 2017, 8(55), 94104-94116.
[http://dx.doi.org/10.18632/oncotarget.21585] [PMID: 29212213]
[119]
Albrecht, B.K.; Gehling, V.S.; Hewitt, M.C.; Vaswani, R.G.; Côté, A.; Leblanc, Y.; Nasveschuk, C.G.; Bellon, S.; Bergeron, L.; Campbell, R.; Cantone, N.; Cooper, M.R.; Cummings, R.T.; Jayaram, H.; Joshi, S.; Mertz, J.A.; Neiss, A.; Normant, E.; O’Meara, M.; Pardo, E.; Poy, F.; Sandy, P.; Supko, J.; Sims, R.J., III; Harmange, J-C.; Taylor, A.M.; Audia, J.E. Identification of a benzoisoxazoloazepine inhibitor (CPI-0610) of the bromodomain and extra-terminal (BET) family as a candidate for human clinical trials. J. Med. Chem., 2016, 59(4), 1330-1339.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01882] [PMID: 26815195]
[120]
Siu, K.T.; Ramachandran, J.; Yee, A.J.; Eda, H.; Santo, L.; Panaroni, C.; Mertz, J.A.; Sims Iii, R.J.; Cooper, M.R.; Raje, N. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia, 2017, 31(8), 1760-1769.
[http://dx.doi.org/10.1038/leu.2016.355] [PMID: 27890933]
[121]
McDaniel, K.F.; Wang, L.; Soltwedel, T.; Fidanze, S.D.; Hasvold, L.A.; Liu, D.; Mantei, R.A.; Pratt, J.K.; Sheppard, G.S.; Bui, M.H.; Faivre, E.J.; Huang, X.; Li, L.; Lin, X.; Wang, R.; Warder, S.E.; Wilcox, D.; Albert, D.H.; Magoc, T.J.; Rajaraman, G.; Park, C.H.; Hutchins, C.W.; Shen, J.J.; Edalji, R.P.; Sun, C.C.; Martin, R.; Gao, W.; Wong, S.; Fang, G.; Elmore, S.W.; Shen, Y.; Kati, W.M. Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a potent and orally available bromodomain and extraterminal domain (BET). J. Med. Chem., 2017, 60(20), 8369-8384.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00746] [PMID: 28949521]
[122]
Vázquez, R.; Civenni, G.; Marchetti, M.; Zadic, S.; Liu, P.; Ruggeri, B.; Carbone, G.M.; Catapano, C.V. Abstract 5080: BET inhibitors INCB054329 and INCB057643 display significant activity in androgen-independent prostate cancer models. Cancer Res., 2017, 77, 5080-5080.
[http://dx.doi.org/10.1158/1538-7445.AM2017-5080]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version480msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[04:36:54] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[04:36:54] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[04:36:54] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (142ms)time
  • Application (338ms)time
  • 1 x Application (70.43%)
    338ms
    1 x Booting (29.57%)
    142ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    37 statements were executed, 4 of which were duplicates, 33 unique. Show only duplicated239ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('316245611','',1,1740458214,1740458214) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740458214
      1.21msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('316245611','/article/94151',1,1740458214,1740458214)
      240μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 316245611 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 316245611) limit 1
      19.46msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 316245611
      • 1: 316245611
      • 2: 316245611
      • 3: 316245611
      • 4: 316245611
      • 5: 316245611
      • 6: 316245611
      • 7: 316245611
      • 8: 316245611
      • 9: 316245611
      • 10: 316245611
      • 11: 316245611
      • 12: 316245611
      • 13: 316245611
      • 14: 316245611
      • 15: 316245611
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=94151
      990μsalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      1.08msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      1.35msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.15msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      3.37msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      2.77msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '94151'
      2.7msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 94151
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '94151'
      3.63msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 94151
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '94151' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      5.98msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 94151
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      330μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      710μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      56.93msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      46.71msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      38.46msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 94151 limit 1
      420μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 94151
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 94151 and content_type = 'article' order by status desc limit 1
      1.77msalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 16 and cd.sub_disease_id = 597 and content_id!=94151 and cd.content_type = 'article' order by rand() limit 20
      29.26msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 166814 limit 1
      350μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 166814
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      340μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      530μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '94151' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      490μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9492' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      400μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2572' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      390μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572)
      8.53msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9492) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9492) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9492)
      870μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94151) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94151) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 316245611 and j.to_ip >=316245611 )) and ((j.from_date <= 1740458214 and j.to_date >= 1740458214 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 94151)
      850μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '6544' and is_uploaded = 1 and issue_id = 9492 order by cast(first_page as SIGNED) desc limit 1
      690μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 6544
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '6563' and is_uploaded = 1 and issue_id = 9492 order by cast(first_page as SIGNED) asc limit 1
      610μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 6563
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      220μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      280μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 94151 limit 1
      2.76msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 94151
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740458214 and `b`.`banner_to_date` >= 1740458214 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.55msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740458214
      • 4: 1740458214
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740458214 and `b`.`banner_to_date` >= 1740458214 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.53msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740458214
      • 4: 1740458214
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='86db1b3323487c2a357eec06ea5d9ac6'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
        _token
        y8MmwRm3WkpPzYJT0w7dkB8lINNFngbDngESmuDI
        uc_cart_id
        86db1b3323487c2a357eec06ea5d9ac6
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/article/94151" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/94151
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IlA2Z1dXazhYQUtOaVlSM09NVno4Mnc9PSIsInZhbHVlIjoiOHFoS0syczRWT2RmTUVadW9BT3BtcitNeXhWQWtZa3VtaW1RMGdrUmRQcz0iLCJtYWMiOiJjMDA4NDU1YjAwYWQyODFjMmNiYjFjODI1MDZlOWRkMTI4YTRkNGQ2OTI4MGMxNTI4MzY4NDUyZjlkOWEwZGFmIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlA2Z1dXazhYQUtOaVlSM09NVno4Mnc9PSIsInZhbHVlIjoiOHFoS0syczRWT2RmTUVadW9BT3BtcitNeXhWQWtZa3VtaW1RMGdrUmRQcz0iLCJtYWMiOiJjMDA4NDU1YjAwYWQy" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 04:36:54 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImlVZWJnQytiNWV6d1lqeXJjenNBRGc9PSIsInZhbHVlIjoiSGx0Z2Y3NTM0a1hyTmgxb3d6K2NpZlhXL25oVVE5bm5zcmlNQk93ZEtCUmFzT1paMWI0VnpZUGQ4blU3UVJjSzlmb2dTaGE0WHNNYktqdllkVWljLzRwb0ZhSjJDRnBiM2dyZ3Z0eWVBdXNkMisxZjlZZG52Nzlnd0NoREhZYVgiLCJtYWMiOiJiOTRiZGY2YjY0NGI2Yzk3Nzc0Zjc1NzFjNjYwMTFiYjM0YjBlN2FjODJhMmVlYTJjMDFkYjZkMzczNGEwNmQ0IiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 16:36:54 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6ImlVZWJnQytiNWV6d1lqeXJjenNBRGc9PSIsInZhbHVlIjoiSGx0Z2Y3NTM0a1hyTmgxb3d6K2NpZlhXL25oVVE5bm5zcmlNQk93ZEtCUmFzT1paMWI0VnpZUGQ4blU3UVJjSzlmb2dTa" 1 => "alphaeurekaselectnet_session=eyJpdiI6Im9XY003QWFYQXMxckZ1WVkvS0ZFa1E9PSIsInZhbHVlIjoibFZUV0ZJK2VlMkU0WHQ4RGpBL0hsQUd1NEphcTNxWmxpb2FwRDJuOXpCV1RFZk1EdzlROHM4T2pBS0xWcE9pcjFwaEYrQXJzN05CZGM5bFA4K0Vab2UrRFoyNlVFRndvblRiKy8vYi9ZNlZqNHBXTGpoanZyMExmeTMrRlFQalUiLCJtYWMiOiIxZDlhZDJjMjE1NmNmYzEyZDdjYzlhZTk0MjFiMTliNWY5MTE1YTI0MjZkYWJlM2Y1NGJlMzYxYzk0ZDllMGIzIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Im9XY003QWFYQXMxckZ1WVkvS0ZFa1E9PSIsInZhbHVlIjoibFZUV0ZJK2VlMkU0WHQ4RGpBL0hsQUd1NEphcTNxWmxpb2FwRDJuOXpCV1RFZk1EdzlROHM4T2p" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6ImlVZWJnQytiNWV6d1lqeXJjenNBRGc9PSIsInZhbHVlIjoiSGx0Z2Y3NTM0a1hyTmgxb3d6K2NpZlhXL25oVVE5bm5zcmlNQk93ZEtCUmFzT1paMWI0VnpZUGQ4blU3UVJjSzlmb2dTaGE0WHNNYktqdllkVWljLzRwb0ZhSjJDRnBiM2dyZ3Z0eWVBdXNkMisxZjlZZG52Nzlnd0NoREhZYVgiLCJtYWMiOiJiOTRiZGY2YjY0NGI2Yzk3Nzc0Zjc1NzFjNjYwMTFiYjM0YjBlN2FjODJhMmVlYTJjMDFkYjZkMzczNGEwNmQ0IiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 16:36:54 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6ImlVZWJnQytiNWV6d1lqeXJjenNBRGc9PSIsInZhbHVlIjoiSGx0Z2Y3NTM0a1hyTmgxb3d6K2NpZlhXL25oVVE5bm5zcmlNQk93ZEtCUmFzT1paMWI0VnpZUGQ4blU3UVJjSzlmb2dTa" 1 => "alphaeurekaselectnet_session=eyJpdiI6Im9XY003QWFYQXMxckZ1WVkvS0ZFa1E9PSIsInZhbHVlIjoibFZUV0ZJK2VlMkU0WHQ4RGpBL0hsQUd1NEphcTNxWmxpb2FwRDJuOXpCV1RFZk1EdzlROHM4T2pBS0xWcE9pcjFwaEYrQXJzN05CZGM5bFA4K0Vab2UrRFoyNlVFRndvblRiKy8vYi9ZNlZqNHBXTGpoanZyMExmeTMrRlFQalUiLCJtYWMiOiIxZDlhZDJjMjE1NmNmYzEyZDdjYzlhZTk0MjFiMTliNWY5MTE1YTI0MjZkYWJlM2Y1NGJlMzYxYzk0ZDllMGIzIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Im9XY003QWFYQXMxckZ1WVkvS0ZFa1E9PSIsInZhbHVlIjoibFZUV0ZJK2VlMkU0WHQ4RGpBL0hsQUd1NEphcTNxWmxpb2FwRDJuOXpCV1RFZk1EdzlROHM4T2p" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "y8MmwRm3WkpPzYJT0w7dkB8lINNFngbDngESmuDI" "uc_cart_id" => "86db1b3323487c2a357eec06ea5d9ac6" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/article/94151" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 04:36:54GET/article/94151314372