Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

Author(s): Jessica Ceramella, Domenico Iacopetta, Alexia Barbarossa, Anna Caruso*, Fedora Grande*, Maria Grazia Bonomo, Annaluisa Mariconda, Pasquale Longo, Saturnino Carmela and Maria Stefania Sinicropi

Volume 20, Issue 6, 2020

Page: [444 - 465] Pages: 22

DOI: 10.2174/1389557520666200117144701

Price: $65

Abstract

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

Keywords: Protein kinases, kinases inhibitors, carbazoles, anticancer drugs, targeted therapy, cancer.

Graphical Abstract

[1]
Gatzka, M.V. Targeted Tumor Therapy Remixed-An Update on the Use of Small-Molecule Drugs in Combination Therapies. Cancers (Basel), 2018, 10(6), E155
[http://dx.doi.org/10.3390/cancers10060155] [PMID: 29794999]
[2]
Dervisis, N.; Klahn, S. Therapeutic Innovations: Tyrosine Kinase Inhibitors in Cancer. Vet. Sci., 2016, 3(1), E4
[http://dx.doi.org/10.3390/vetsci3010004] [PMID: 29056714]
[3]
Arora, A.; Scholar, E.M. Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther., 2005, 315(3), 971-979.
[http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463]
[4]
Pearson, M.A.; Fabbro, D. Targeting protein kinases in cancer therapy: A success? Expert Rev. Anticancer Ther., 2004, 4(6), 1113-1124.
[http://dx.doi.org/10.1586/14737140.4.6.1113] [PMID: 15606337]
[5]
Blume-Jensen, P.; Hunter, T. Oncogenic kinase signalling. Nature, 2001, 411(6835), 355-365.
[http://dx.doi.org/10.1038/35077225] [PMID: 11357143]
[6]
García-Aranda, M.; Redondo, M. Protein kinase targets in breast cancer. Int. J. Mol. Sci., 2017, 18(12), 1-31.
[http://dx.doi.org/10.3390/ijms18122543] [PMID: 29186886]
[7]
Kissau, L.; Stahl, P.; Mazitschek, R.; Giannis, A.; Waldmann, H. Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold. J. Med. Chem., 2003, 46(14), 2917-2931.
[http://dx.doi.org/10.1021/jm0307943] [PMID: 12825933]
[8]
Bari, S.B.; Adhikari, S.; Surana, S.J. Tyrosine Kinase Receptor Inhibitors: A new target for anticancer drug development. J. Pharm. Sci. Technol., 2012, 1(2), 36-45.
[9]
Sinicropi, M.S.; Caruso, A.; Conforti, F.; Marrelli, M.; El Kashef, H.; Lancelot, J.C.; Rault, S.; Statti, G.A.; Menichini, F. Synthesis, inhibition of NO production and antiproliferative activities of some indole derivatives. J. Enzyme Inhib. Med. Chem., 2009, 24(5), 1148-1153.
[http://dx.doi.org/10.1080/14756360802693890] [PMID: 19555184]
[10]
Lappano, R.; Santolla, M.F.; Pupo, M.; Sinicropi, M.S.; Caruso, A.; Rosano, C.; Maggiolini, M. MIBE acts as antagonist ligand of both estrogen receptor α and GPER in breast cancer cells. Breast Cancer Res., 2012, 14(1), R12.
[http://dx.doi.org/10.1186/bcr3096] [PMID: 22251451]
[11]
Caruso, A.; Chimento, A.; El-Kashef, H.; Lancelot, J.C.; Panno, A.; Pezzi, V.; Saturnino, C.; Sinicropi, M.S.; Sirianni, R.; Rault, S. Antiproliferative activity of some 1,4-dimethylcarbazoles on cells that express estrogen receptors: part I. J. Enzyme Inhib. Med. Chem., 2012, 27(4), 609-613.
[http://dx.doi.org/10.3109/14756366.2011.603132] [PMID: 21883039]
[12]
Caruso, A.; Sinicropi, M.S.; Lancelot, J.C.; El-Kashef, H.; Saturnino, C.; Aubert, G.; Ballandonne, C.; Lesnard, A.; Cresteil, T.; Dallemagne, P.; Rault, S. Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles. Bioorg. Med. Chem. Lett., 2014, 24(2), 467-472.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.047] [PMID: 24374274]
[13]
Rizza, P.; Pellegrino, M.; Caruso, A.; Iacopetta, D.; Sinicropi, M.S.; Rault, S.; Lancelot, J.C.; El-Kashef, H.; Lesnard, A.; Rochais, C.; Dallemagne, P.; Saturnino, C.; Giordano, F.; Catalano, S.; Andò, S. 3-(Dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (DPA-HBFQ-1) plays an inhibitory role on breast cancer cell growth and progression. Eur. J. Med. Chem., 2016, 107, 275-287.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.004] [PMID: 26599533]
[14]
Caruso, A.; Lancelot, J.; El-Kashef, H.; Sinicropi, M.S.; Legay, R.; Lesnard, A.; Rault, S. A rapid and versatile synthesis of novel pyrimido[5,4-b]carbazoles. Tetrahedron, 2009, 65, 10400-10405.
[http://dx.doi.org/10.1016/j.tet.2009.10.025]
[15]
Caruso, A.; Lancelot, J.C.; El-Kashef, H.; Panno, A.; Sinicropi, M.S.; Legay, R.; Lesnard, A.; Lepailleur, A.; Rault, S. Four Partners, Three-Step, One-Pot Reaction for a Library of New 2-Alkyl(dialkyl)aminoquinazolin-4(3H)-ones. J. Heterocycl. Chem., 2014, 51, 282-293.
[http://dx.doi.org/10.1002/jhet.1942]
[16]
Panno, A.; Sinicropi, M.S.; Caruso, A.; El-Kashef, H.; Lancelot, J.C.; Aubert, G.; Lesnard, A.; Cresteil, T.; Rault, S. New Trimethoxybenzamides and Trimethoxyphenylureas derived from dimethylcarbazole as cytotoxic agents. Part I. J. Heterocycl. Chem., 2014, 51, 294-302.
[http://dx.doi.org/10.1002/jhet.1951]
[17]
Saturnino, C.; Caruso, A.; Iacopetta, D.; Rosano, C.; Ceramella, J.; Muià, N.; Mariconda, A.; Bonomo, M.G.; Ponassi, M.; Rosace, G.; Sinicropi, M.S.; Longo, P. Inhibition of Human Topoisomerase II by N,N,N-Trimethylethanammonium Iodide Alkylcarbazole Derivatives. ChemMedChem, 2018, 13(24), 2635-2643.
[http://dx.doi.org/10.1002/cmdc.201800546] [PMID: 30347518]
[18]
Sinicropi, M.S.; Lappano, R.; Caruso, A.; Santolla, M.F.; Pisano, A.; Rosano, C.; Capasso, A.; Panno, A.; Lancelot, J.C.; Rault, S.; Saturnino, C.; Maggiolini, M. (6-bromo-1,4-dimethyl-9H-carbazol-3-yl-methylene)-hydrazine (carbhydraz) acts as a GPER agonist in breast cancer cells. Curr. Top. Med. Chem., 2015, 15(11), 1035-1042.
[http://dx.doi.org/10.2174/1568026615666150317221549] [PMID: 25786510]
[19]
Saturnino, C.; Caruso, A.; Longo, P.; Capasso, A.; Pingitore, A.; Caroleo, M.C.; Cione, E.; Perri, M.; Nicolo, F.; Nardo, V.M.; Scolaro, L.M.; Sinicropi, M.S.; Plutino, M.R.; El-Kashef, H. Crystallographic study and biological evaluation of 1,4-dimethyl-N-alkylcarbazoles. Curr. Top. Med. Chem., 2015, 15(11), 973-979.
[http://dx.doi.org/10.2174/1568026615666150317222444] [PMID: 25786507]
[20]
Saturnino, C.; Iacopetta, D.; Sinicropi, M.S.; Rosano, C.; Caruso, A.; Caporale, A.; Marra, N.; Marengo, B.; Pronzato, M.A.; Parisi, O.I.; Longo, P.; Ricciarelli, R. N-alkyl carbazole derivatives as new tools for Alzheimer’s disease: preliminary studies. Molecules, 2014, 19(7), 9307-9317.
[http://dx.doi.org/10.3390/molecules19079307] [PMID: 24991761]
[21]
Caruso, A.; Iacopetta, D.; Puoci, F.; Cappello, A.R.; Saturnino, C.; Sinicropi, M.S. Carbazole derivatives: a promising scenario for breast cancer treatment. Mini Rev. Med. Chem., 2016, 16(8), 630-643.
[http://dx.doi.org/10.2174/1389557515666150709111342] [PMID: 26156543]
[22]
Iacopetta, D.; Rosano, C.; Puoci, F.; Parisi, O.I.; Saturnino, C.; Caruso, A.; Longo, P.; Ceramella, J.; Malzert-Fréon, A.; Dallemagne, P.; Rault, S.; Sinicropi, M.S. Multifaceted properties of 1,4-dimethylcarbazoles: Focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors. Eur. J. Pharm. Sci., 2017, 96, 263-272.
[http://dx.doi.org/10.1016/j.ejps.2016.09.039] [PMID: 27702608]
[23]
Maji, B.; Kumar, K.; Muniyappa, K.; Bhattacharya, S. New dimeric carbazole-benzimidazole mixed ligands for the stabilization of human telomeric G-quadruplex DNA and as telomerase inhibitors. A remarkable influence of the spacer. Org. Biomol. Chem., 2015, 13(30), 8335-8348.
[http://dx.doi.org/10.1039/C5OB00675A] [PMID: 26149178]
[24]
Sinicropi, M.S.; Iacopetta, D.; Rosano, C.; Randino, R.; Caruso, A.; Saturnino, C.; Muià, N.; Ceramella, J.; Puoci, F.; Rodriquez, M.; Longo, P.; Plutino, M.R. N-thioalkylcarbazoles derivatives as new anti-proliferative agents: synthesis, characterisation and molecular mechanism evaluation. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 434-444.
[http://dx.doi.org/10.1080/14756366.2017.1419216] [PMID: 29383954]
[25]
Saturnino, C.; Palladino, C.; Napoli, M.; Sinicropi, M.S.; Botta, A.; Sala, M.; Carcereri de Prati, A.; Novellino, E.; Suzuki, H. Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: preliminary study. Eur. J. Med. Chem., 2013, 60, 112-119.
[http://dx.doi.org/10.1016/j.ejmech.2012.11.004] [PMID: 23287056]
[26]
Parisi, O.I.; Morelli, C.; Puoci, F.; Saturnino, C.; Caruso, A.; Sisci, D.; Trombino, G.E.; Picci, N.; Sinicropi, M.S. Magnetic molecularly imprinted polymers (MMIPs) for carbazole derivative release in targeted cancer therapy. J. Mater. Chem. B Mater. Biol. Med., 2014, 2(38), 6619-6625.
[http://dx.doi.org/10.1039/C4TB00607K]
[27]
Grande, F.; Rizzuti, B.; Occhiuzzi, M.A.; Ioele, G.; Casacchia, T.; Gelmini, F.; Guzzi, R.; Garofalo, A.; Statti, G. Identification by Molecular Docking ofHomoisoflavones from Leopoldia comosa as Ligands of Estrogen Receptors. Molecules, 2018, 23(4)E894
[http://dx.doi.org/10.3390/molecules23040894] [PMID: 29649162]
[28]
Casacchia, T.; Occhiuzzi, M.A.; Grande, F.; Rizzuti, B.; Granieri, M.C.; Rocca, C.; Gattuso, A.; Garofalo, A.; Angelone, T.; Statti, G. A pilot study on the nutraceutical properties of the Citrus hybrid Tacle (R) as a dietary source of polyphenols for supplementation in metabolic disorders. J. Funct. Foods, 2019, 52, 370-381.
[http://dx.doi.org/10.1016/j.jff.2018.11.030]
[29]
Bossemeyer, D. Protein kinases--structure and function. FEBS Lett., 1995, 369(1), 57-61.
[http://dx.doi.org/10.1016/0014-5793(95)00580-3] [PMID: 7641885]
[30]
Knighton, D.R.; Zheng, J.H.; Ten Eyck, L.F.; Ashford, V.A.; Xuong, N.H.; Taylor, S.S.; Sowadski, J.M. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science, 1991, 253(5018), 407-414.
[http://dx.doi.org/10.1126/science.1862342] [PMID: 1862342]
[31]
Krause, D.S.; Van Etten, R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med., 2005, 353(2), 172-187.
[http://dx.doi.org/10.1056/NEJMra044389] [PMID: 16014887]
[32]
Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science, 2002, 298(5600), 1912-1934.
[http://dx.doi.org/10.1126/science.1075762] [PMID: 12471243]
[33]
Fabbro, D.; Cowan-Jacob, S.W.; Moebitz, H. Ten things you should know about protein kinases: IUPHAR Review 14. Br. J. Pharmacol., 2015, 172(11), 2675-2700.
[http://dx.doi.org/10.1111/bph.13096] [PMID: 25630872]
[34]
Bhullar, K.S.; Lagarón, N.O.; McGowan, E.M.; Parmar, I.; Jha, A.; Hubbard, B.P.; Rupasinghe, H.P.V. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol. Cancer, 2018, 17(1), 48.
[http://dx.doi.org/10.1186/s12943-018-0804-2] [PMID: 29455673]
[35]
Blagden, S.; de Bono, J. Drugging cell cycle kinases in cancer therapy. Curr. Drug Targets, 2005, 6(3), 325-335.
[http://dx.doi.org/10.2174/1389450053765824] [PMID: 15857291]
[36]
Paul, M.K.; Mukhopadhyay, A.K. Tyrosine kinase - Role and significance in Cancer. Int. J. Med. Sci., 2004, 1(2), 101-115.
[http://dx.doi.org/10.7150/ijms.1.101] [PMID: 15912202]
[37]
Fehm, T.; Jäger, W.; Krämer, S.; Sohn, C.; Solomayer, E.; Wallwiener, D.; Gebauer, G. Prognostic significance of serum HER2 and CA 15-3 at the time of diagnosis of metastatic breast cancer. Anticancer Res., 2004, 24(3b), 1987-1992.
[PMID: 15274389]
[38]
Cheng, H.C.; Qi, R.Z.; Paudel, H.; Zhu, H.J. Regulation and function of protein kinases and phosphatases. Enzyme Res., 2011, 2011794089
[http://dx.doi.org/10.4061/2011/794089] [PMID: 22195276]
[39]
Cheetham, G.M. Novel protein kinases and molecular mechanisms of autoinhibition. Curr. Opin. Struct. Biol., 2004, 14(6), 700-705.
[http://dx.doi.org/10.1016/j.sbi.2004.10.011] [PMID: 15582394]
[40]
Kondapalli, L.; Soltani, K.; Lacouture, M.E. The promise of molecular targeted therapies: protein kinase inhibitors in the treatment of cutaneous malignancies. J. Am. Acad. Dermatol., 2005, 53(2), 291-302.
[http://dx.doi.org/10.1016/j.jaad.2005.02.011] [PMID: 16021125]
[41]
Cohen, P. Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov., 2002, 1(4), 309-315.
[http://dx.doi.org/10.1038/nrd773] [PMID: 12120282]
[42]
Melnikova, I.; Golden, J. Targeting protein kinases. Nat. Rev. Drug Discov., 2004, 3(12), 993-994.
[http://dx.doi.org/10.1038/nrd1600] [PMID: 15645605]
[43]
Vlahovic, G.; Crawford, J. Activation of tyrosine kinases in cancer. Oncologist, 2003, 8(6), 531-538.
[http://dx.doi.org/10.1634/theoncologist.8-6-531] [PMID: 14657531]
[44]
Segovia-Mendoza, M.; González-González, M.E.; Barrera, D.; Díaz, L.; García-Becerra, R. Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence. Am. J. Cancer Res., 2015, 5(9), 2531-2561.
[PMID: 26609467]
[45]
Zhang, J.; Yang, P.L.; Gray, N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer, 2009, 9(1), 28-39.
[http://dx.doi.org/10.1038/nrc2559] [PMID: 19104514]
[46]
Midland, A.A.; Whittle, M.C.; Duncan, J.S.; Abell, A.N.; Nakamura, K.; Zawistowski, J.S.; Carey, L.A.; Earp, H.S., III; Graves, L.M.; Gomez, S.M.; Johnson, G.L. Defining the expressed breast cancer kinome. Cell Res., 2012, 22(4), 620-623.
[http://dx.doi.org/10.1038/cr.2012.25] [PMID: 22310242]
[47]
Davis, M.I.; Hunt, J.P.; Herrgard, S.; Ciceri, P.; Wodicka, L.M.; Pallares, G.; Hocker, M.; Treiber, D.K.; Zarrinkar, P.P. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 2011, 29(11), 1046-1051.
[http://dx.doi.org/10.1038/nbt.1990] [PMID: 22037378]
[48]
Knight, Z.A.; Shokat, K.M. Features of selective kinase inhibitors. Chem. Biol., 2005, 12(6), 621-637.
[http://dx.doi.org/10.1016/j.chembiol.2005.04.011] [PMID: 15975507]
[49]
Force, T.; Kolaja, K.L. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat. Rev. Drug Discov., 2011, 10(2), 111-126.
[http://dx.doi.org/10.1038/nrd3252] [PMID: 21283106]
[50]
Hasinoff, B.B. The cardiotoxicity and myocyte damage caused by small molecule anticancer tyrosine kinase inhibitors is correlated with lack of target specificity. Toxicol. Appl. Pharmacol., 2010, 244(2), 190-195.
[http://dx.doi.org/10.1016/j.taap.2009.12.032] [PMID: 20045709]
[51]
Cutolo, M. The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: latest findings and clinical potential. Ther. Adv. Musculoskelet. Dis., 2013, 5(1), 3-11.
[http://dx.doi.org/10.1177/1759720X12470753] [PMID: 23515130]
[52]
Zuccotto, F.; Ardini, E.; Casale, E.; Angiolini, M. Through the “gatekeeper door”: exploiting the active kinase conformation. J. Med. Chem., 2010, 53(7), 2681-2694.
[http://dx.doi.org/10.1021/jm901443h] [PMID: 20000735]
[53]
Kufareva, I.; Abagyan, R. Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states. J. Med. Chem., 2008, 51(24), 7921-7932.
[http://dx.doi.org/10.1021/jm8010299] [PMID: 19053777]
[54]
Davies, S.P.; Reddy, H.; Caivano, M.; Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J., 2000, 351(Pt 1), 95-105.
[http://dx.doi.org/10.1042/bj3510095] [PMID: 10998351]
[55]
Liu, Y.; Gray, N.S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol., 2006, 2(7), 358-364.
[http://dx.doi.org/10.1038/nchembio799] [PMID: 16783341]
[56]
Wise, D.R.; Thompson, C.B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci., 2010, 35(8), 427-433.
[http://dx.doi.org/10.1016/j.tibs.2010.05.003] [PMID: 20570523]
[57]
Nagar, B.; Bornmann, W.G.; Pellicena, P.; Schindler, T.; Veach, D.R.; Miller, W.T.; Clarkson, B.; Kuriyan, J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res., 2002, 62(15), 4236-4243.
[PMID: 12154025]
[58]
Schindler, T.; Bornmann, W.; Pellicena, P.; Miller, W.T.; Clarkson, B.; Kuriyan, J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science, 2000, 289(5486), 1938-1942.
[http://dx.doi.org/10.1126/science.289.5486.1938] [PMID: 10988075]
[59]
Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P.F.; Gilmore, T.; Graham, A.G.; Grob, P.M.; Hickey, E.R.; Moss, N.; Pav, S.; Regan, J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat. Struct. Biol., 2002, 9(4), 268-272.
[http://dx.doi.org/10.1038/nsb770] [PMID: 11896401]
[60]
Wan, P.T.; Garnett, M.J.; Roe, S.M.; Lee, S.; Niculescu-Duvaz, D.; Good, V.M.; Jones, C.M.; Marshall, C.J.; Springer, C.J.; Barford, D.; Marais, R.; Cancer Genome, P. Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 2004, 116(6), 855-867.
[http://dx.doi.org/10.1016/S0092-8674(04)00215-6] [PMID: 15035987]
[61]
Manley, P.W.; Bold, G.; Brüggen, J.; Fendrich, G.; Furet, P.; Mestan, J.; Schnell, C.; Stolz, B.; Meyer, T.; Meyhack, B.; Stark, W.; Strauss, A.; Wood, J. Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. Biochim. Biophys. Acta, 2004, 1697(1-2), 17-27.
[http://dx.doi.org/10.1016/j.bbapap.2003.11.010] [PMID: 15023347]
[62]
Ohren, J.F.; Chen, H.; Pavlovsky, A.; Whitehead, C.; Zhang, E.; Kuffa, P.; Yan, C.; McConnell, P.; Spessard, C.; Banotai, C.; Mueller, W.T.; Delaney, A.; Omer, C.; Sebolt-Leopold, J.; Dudley, D.T.; Leung, I.K.; Flamme, C.; Warmus, J.; Kaufman, M.; Barrett, S.; Tecle, H.; Hasemann, C.A. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat. Struct. Mol. Biol., 2004, 11(12), 1192-1197.
[http://dx.doi.org/10.1038/nsmb859] [PMID: 15543157]
[63]
Allen, L.F.; Sebolt-Leopold, J.; Meyer, M.B. CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Semin. Oncol., 2003, 30(5)(Suppl. 16), 105-116.
[http://dx.doi.org/10.1053/j.seminoncol.2003.08.012] [PMID: 14613031]
[64]
Eglen, R.; Reisine, T. Drug discovery and the human kinome: recent trends. Pharmacol. Ther., 2011, 130(2), 144-156.
[http://dx.doi.org/10.1016/j.pharmthera.2011.01.007] [PMID: 21256157]
[65]
Adrián, F.J.; Ding, Q.; Sim, T.; Velentza, A.; Sloan, C.; Liu, Y.; Zhang, G.; Hur, W.; Ding, S.; Manley, P.; Mestan, J.; Fabbro, D.; Gray, N.S. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nat. Chem. Biol., 2006, 2(2), 95-102.
[http://dx.doi.org/10.1038/nchembio760] [PMID: 16415863]
[66]
Dong, Q.; Dougan, D.R.; Gong, X.; Halkowycz, P.; Jin, B.; Kanouni, T.; O’Connell, S.M.; Scorah, N.; Shi, L.; Wallace, M.B.; Zhou, F. Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer. Bioorg. Med. Chem. Lett., 2011, 21(5), 1315-1319.
[http://dx.doi.org/10.1016/j.bmcl.2011.01.071] [PMID: 21310613]
[67]
Schadendorf, D.; Amonkar, M.M.; Milhem, M.; Grotzinger, K.; Demidov, L.V.; Rutkowski, P.; Garbe, C.; Dummer, R.; Hassel, J.C.; Wolter, P.; Mohr, P.; Trefzer, U.; Lefeuvre-Plesse, C.; Rutten, A.; Steven, N.; Ullenhag, G.; Sherman, L.; Wu, F.S.; Patel, K.; Casey, M.; Robert, C. Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study. Ann. Oncol., 2014, 25(3), 700-706.
[http://dx.doi.org/10.1093/annonc/mdt580] [PMID: 24504441]
[68]
Grimsby, J.; Sarabu, R.; Corbett, W.L.; Haynes, N.E.; Bizzarro, F.T.; Coffey, J.W.; Guertin, K.R.; Hilliard, D.W.; Kester, R.F.; Mahaney, P.E.; Marcus, L.; Qi, L.; Spence, C.L.; Tengi, J.; Magnuson, M.A.; Chu, C.A.; Dvorozniak, M.T.; Matschinsky, F.M.; Grippo, J.F. Allosteric activators of glucokinase: potential role in diabetes therapy. Science, 2003, 301(5631), 370-373.
[http://dx.doi.org/10.1126/science.1084073] [PMID: 12869762]
[69]
Guertin, K.R.; Grimsby, J. Small molecule glucokinase activators as glucose lowering agents: a new paradigm for diabetes therapy. Curr. Med. Chem., 2006, 13(15), 1839-1843.
[http://dx.doi.org/10.2174/092986706777452551] [PMID: 16787225]
[70]
Cohen, M.S.; Zhang, C.; Shokat, K.M.; Taunton, J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science, 2005, 308(5726), 1318-1321.
[http://dx.doi.org/10.1126/science1108367] [PMID: 15919995]
[71]
Kwak, E.L.; Sordella, R.; Bell, D.W.; Godin-Heymann, N.; Okimoto, R.A.; Brannigan, B.W.; Harris, P.L.; Driscoll, D.R.; Fidias, P.; Lynch, T.J.; Rabindran, S.K.; McGinnis, J.P.; Wissner, A.; Sharma, S.V.; Isselbacher, K.J.; Settleman, J.; Haber, D.A. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. USA, 2005, 102(21), 7665-7670.
[http://dx.doi.org/10.1073/pnas.0502860102] [PMID: 15897464]
[72]
Blanc, J.; Geney, R.; Menet, C. Type II kinase inhibitors: an opportunity in cancer for rational design. Anticancer. Agents Med. Chem., 2013, 13(5), 731-747.
[http://dx.doi.org/10.2174/1871520611313050008] [PMID: 23094911]
[73]
Leproult, E.; Barluenga, S.; Moras, D.; Wurtz, J.M.; Winssinger, N. Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J. Med. Chem., 2011, 54(5), 1347-1355.
[http://dx.doi.org/10.1021/jm101396q] [PMID: 21322567]
[74]
Liu, Q.; Sabnis, Y.; Zhao, Z.; Zhang, T.; Buhrlage, S.J.; Jones, L.H.; Gray, N.S. Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol., 2013, 20(2), 146-159.
[http://dx.doi.org/10.1016/j.chembiol.2012.12.006] [PMID: 23438744]
[75]
Singh, J.; Petter, R.C.; Baillie, T.A.; Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov., 2011, 10(4), 307-317.
[http://dx.doi.org/10.1038/nrd3410] [PMID: 21455239]
[76]
Barf, T.; Kaptein, A. Irreversible protein kinase inhibitors: balancing the benefits and risks. J. Med. Chem., 2012, 55(14), 6243-6262.
[http://dx.doi.org/10.1021/jm3003203] [PMID: 22621397]
[77]
Zhao, Z.; Liu, Q.; Bliven, S.; Xie, L.; Bourne, P.E. Determining cysteines available for covalent inhibition across the human kinome. J. Med. Chem., 2017, 60(7), 2879-2889.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01815] [PMID: 28326775]
[78]
Rabindran, S.K.; Discafani, C.M.; Rosfjord, E.C.; Baxter, M.; Floyd, M.B.; Golas, J.; Hallett, W.A.; Johnson, B.D.; Nilakantan, R.; Overbeek, E.; Reich, M.F.; Shen, R.; Shi, X.; Tsou, H.R.; Wang, Y.F.; Wissner, A. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res., 2004, 64(11), 3958-3965.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-2868] [PMID: 15173008]
[79]
Kobayashi, S.; Ji, H.; Yuza, Y.; Meyerson, M.; Wong, K.K.; Tenen, D.G.; Halmos, B. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res., 2005, 65(16), 7096-7101.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1346] [PMID: 16103058]
[80]
Liao, B.C.; Lin, C.C.; Yang, J.C. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr. Opin. Oncol., 2015, 27(2), 94-101.
[http://dx.doi.org/10.1097/CCO.0000000000000164] [PMID: 25611025]
[81]
Wang, A.; Yan, X.E.; Wu, H.; Wang, W.; Hu, C.; Chen, C.; Zhao, Z.; Zhao, P.; Li, X.; Wang, L.; Wang, B.; Ye, Z.; Wang, J.; Wang, C.; Zhang, W.; Gray, N.S.; Weisberg, E.L.; Chen, L.; Liu, J.; Yun, C.H.; Liu, Q. Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation. Oncotarget, 2016, 7(43), 69760-69769.
[http://dx.doi.org/10.18632/oncotarget.11951] [PMID: 27626175]
[82]
Akué-Gédu, R.; Rossignol, E.; Azzaro, S.; Knapp, S.; Filippakopoulos, P.; Bullock, A.N.; Bain, J.; Cohen, P.; Prudhomme, M.; Anizon, F.; Moreau, P. Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors. J. Med. Chem., 2009, 52(20), 6369-6381.
[http://dx.doi.org/10.1021/jm901018f] [PMID: 19788246]
[83]
Akué-Gédu, R.; Nauton, L.; Théry, V.; Bain, J.; Cohen, P.; Anizon, F.; Moreau, P. Synthesis, Pim kinase inhibitory potencies and in vitro antiproliferative activities of diversely substituted pyrrolo[2,3-a]carbazoles. Bioorg. Med. Chem., 2010, 18(18), 6865-6873.
[http://dx.doi.org/10.1016/j.bmc.2010.07.036] [PMID: 20728368]
[84]
Giraud, F.; Akué-Gédu, R.; Nauton, L.; Candelon, N.; Debiton, E.; Théry, V.; Anizon, F.; Moreau, P. Synthesis and biological activities of 4-substituted pyrrolo[2,3-a]carbazole Pim kinase inhibitors. Eur. J. Med. Chem., 2012, 56, 225-236.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.029] [PMID: 22982527]
[85]
Akué-Gédu, R.; Letribot, B.; Saugues, E.; Debiton, E.; Anizon, F.; Moreau, P. Kinase inhibitory potencies and in vitro antiproliferative activities of N-10 substituted pyrrolo[2,3-a]carbazole derivatives. Bioorg. Med. Chem. Lett., 2012, 22(11), 3807-3809.
[http://dx.doi.org/10.1016/j.bmcl.2012.03.098] [PMID: 22543026]
[86]
Letribot, B.; Akué-Gédu, R.; Santio, N.M.; El-Ghozzi, M.; Avignant, D.; Cisnetti, F.; Koskinen, P.J.; Gautier, A.; Anizon, F.; Moreau, P. Use of copper(I) catalyzed azide alkyne cycloaddition (CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole Pim kinase inhibitors. Eur. J. Med. Chem., 2012, 50, 304-310.
[http://dx.doi.org/10.1016/j.ejmech.2012.02.009] [PMID: 22386260]
[87]
Suchaud, V.; Gavara, L.; Saugues, E.; Nauton, L.; Théry, V.; Anizon, F.; Moreau, P. Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors. Bioorg. Med. Chem., 2013, 21(14), 4102-4111.
[http://dx.doi.org/10.1016/j.bmc.2013.05.011] [PMID: 23735828]
[88]
Hénon, H.; Anizon, F.; Golsteyn, R.M.; Léonce, S.; Hofmann, R.; Pfeiffer, B.; Prudhomme, M. Synthesis and biological evaluation of new dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted with various saturated and unsaturated side chains via palladium catalyzed cross-coupling reactions. Bioorg. Med. Chem., 2006, 14(11), 3825-3834.
[http://dx.doi.org/10.1016/j.bmc.2006.01.030] [PMID: 16460946]
[89]
Hénon, H.; Messaoudi, S.; Anizon, F.; Aboab, B.; Kucharczyk, N.; Léonce, S.; Golsteyn, R.M.; Pfeiffer, B.; Prudhomme, M. Bis-imide granulatimide analogues as potent Checkpoint 1 kinase inhibitors. Eur. J. Pharmacol., 2007, 554(2-3), 106-112.
[http://dx.doi.org/10.1016/j.ejphar.2006.10.022] [PMID: 17134696]
[90]
Conchon, E.; Anizon, F.; Aboab, B.; Prudhomme, M. Synthesis and biological activities of new checkpoint kinase 1 inhibitors structurally related to granulatimide. J. Med. Chem., 2007, 50(19), 4669-4680.
[http://dx.doi.org/10.1021/jm070664k] [PMID: 17722905]
[91]
Conchon, E.; Anizon, F.; Aboab, B.; Golsteyn, R.M.; Léonce, S.; Pfeiffer, B.; Prudhomme, M. Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone. Eur. J. Med. Chem., 2008, 43(2), 282-292.
[http://dx.doi.org/10.1016/j.ejmech.2007.03.026] [PMID: 17502122]
[92]
Conchon, E.; Anizon, F.; Aboab, B.; Golsteyn, R.M.; Léonce, S.; Pfeiffer, B.; Prudhomme, M. Synthesis, checkpoint kinase 1 inhibitory properties and in vitro antiproliferative activities of new pyrrolocarbazoles. Bioorg. Med. Chem., 2008, 16(8), 4419-4430.
[http://dx.doi.org/10.1016/j.bmc.2008.02.061] [PMID: 18321713]
[93]
Smaill, J.B.; Lee, H.H.; Palmer, B.D.; Thompson, A.M.; Squire, C.J.; Baker, E.N.; Booth, R.J.; Kraker, A.; Hook, K.; Denny, W.A. Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases. Bioorg. Med. Chem. Lett., 2008, 18(3), 929-933.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.046] [PMID: 18191399]
[94]
Lefoix, M.; Coudert, G.; Routier, S.; Pfeiffer, B.; Caignard, D.H.; Hickman, J.; Pierré, A.; Golsteyn, R.M.; Léonce, S.; Bossard, C.; Mérour, J.Y. Novel 5-azaindolocarbazoles as cytotoxic agents and Chk1 inhibitors. Bioorg. Med. Chem., 2008, 16(9), 5303-5321.
[http://dx.doi.org/10.1016/j.bmc.2008.02.086] [PMID: 18342518]
[95]
Conchon, E.; Anizon, F.; Golsteyn, R.M.; Leonce, S.; Pfeiffer, B.; Prudhomme, M. Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of dipyrrolo[3,4-a:3,4-c]carbazole-triones. Tetrahedron, 2006, 62(48), 11136-11144.
[http://dx.doi.org/10.1016/j.tet.2006.09.027]
[96]
Shah, N.; Pang, B.; Yeoh, K.G.; Thorn, S.; Chen, C.S.; Lilly, M.B.; Salto-Tellez, M. Potential roles for the PIM1 kinase in human cancer - a molecular and therapeutic appraisal. Eur. J. Cancer, 2008, 44(15), 2144-2151.
[http://dx.doi.org/10.1016/j.ejca.2008.06.044] [PMID: 18715779]
[97]
Morishita, D.; Katayama, R.; Sekimizu, K.; Tsuruo, T.; Fujita, N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res., 2008, 68(13), 5076-5085.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0634] [PMID: 18593906]
[98]
Fox, C.J.; Hammerman, P.S.; Cinalli, R.M.; Master, S.R.; Chodosh, L.A.; Thompson, C.B. The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev., 2003, 17(15), 1841-1854.
[http://dx.doi.org/10.1101/gad.1105003] [PMID: 12869584]
[99]
Aho, T.L.; Sandholm, J.; Peltola, K.J.; Mankonen, H.P.; Lilly, M.; Koskinen, P.J. Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett., 2004, 571(1-3), 43-49.
[http://dx.doi.org/10.1016/j.febslet.2004.06.050] [PMID: 15280015]
[100]
Zheng, H.C.; Tsuneyama, K.; Takahashi, H.; Miwa, S.; Sugiyama, T.; Popivanova, B.K.; Fujii, C.; Nomoto, K.; Mukaida, N.; Takano, Y. Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression. J. Cancer Res. Clin. Oncol., 2008, 134(4), 481-488.
[http://dx.doi.org/10.1007/s00432-007-0310-1] [PMID: 17876606]
[101]
Li, Y.Y.; Wu, Y.; Tsuneyama, K.; Baba, T.; Mukaida, N. Essential contribution of Ets-1 to constitutive Pim-3 expression in human pancreatic cancer cells. Cancer Sci., 2009, 100(3), 396-404.
[http://dx.doi.org/10.1111/j.1349-7006.2008.01059.x] [PMID: 19154409]
[102]
Popivanova, B.K.; Li, Y.Y.; Zheng, H.; Omura, K.; Fujii, C.; Tsuneyama, K.; Mukaida, N. Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis. Cancer Sci., 2007, 98(3), 321-328.
[http://dx.doi.org/10.1111/j.1349-7006.2007.00390.x] [PMID: 17270021]
[103]
Bartek, J.; Lukas, J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell, 2003, 3(5), 421-429.
[http://dx.doi.org/10.1016/S1535-6108(03)00110-7] [PMID: 12781359]
[104]
Zhang, Y.; Hunter, T. Roles of Chk1 in cell biology and cancer therapy. Int. J. Cancer, 2014, 134(5), 1013-1023.
[http://dx.doi.org/10.1002/ijc.28226] [PMID: 23613359]
[105]
Merry, C.; Fu, K.; Wang, J.; Yeh, I.J.; Zhang, Y. Targeting the checkpoint kinase Chk1 in cancer therapy. Cell Cycle, 2010, 9(2), 279-283.
[http://dx.doi.org/10.4161/cc.9.2.10445] [PMID: 20023404]
[106]
Jiang, X.; Zhao, B.; Britton, R.; Lim, L.Y.; Leong, D.; Sanghera, J.S.; Zhou, B.B.; Piers, E.; Andersen, R.J.; Roberge, M. Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. Mol. Cancer Ther., 2004, 3(10), 1221-1227.
[PMID: 15486189]
[107]
Zhao, B.; Bower, M.J.; McDevitt, P.J.; Zhao, H.; Davis, S.T.; Johanson, K.O.; Green, S.M.; Concha, N.O.; Zhou, B.B. Structural basis for Chk1 inhibition by UCN-01. J. Biol. Chem., 2002, 277(48), 46609-46615.
[http://dx.doi.org/10.1074/jbc.M201233200] [PMID: 12244092]
[108]
Smaill, J.B.; Baker, E.N.; Booth, R.J.; Bridges, A.J.; Dickson, J.M.; Dobrusin, E.M.; Ivanovic, I.; Kraker, A.J.; Lee, H.H.; Lunney, E.A.; Ortwine, D.F.; Palmer, B.D.; Quin, J., III; Squire, C.J.; Thompson, A.M.; Denny, W.A. Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases. Eur. J. Med. Chem., 2008, 43(6), 1276-1296.
[http://dx.doi.org/10.1016/j.ejmech.2007.07.016] [PMID: 17869387]
[109]
Gingrich, D.E.; Reddy, D.R.; Iqbal, M.A.; Singh, J.; Aimone, L.D.; Angeles, T.S.; Albom, M.; Yang, S.; Ator, M.A.; Meyer, S.L.; Robinson, C.; Ruggeri, B.A.; Dionne, C.A.; Vaught, J.L.; Mallamo, J.P.; Hudkins, R.L. A new class of potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the identification of CEP-5214 and its dimethylglycine ester prodrug clinical candidate CEP-7055. J. Med. Chem., 2003, 46(25), 5375-5388.
[http://dx.doi.org/10.1021/jm0301641] [PMID: 14640546]
[110]
Becknell, N.C.; Zulli, A.L.; Angeles, T.S.; Yang, S.; Albom, M.S.; Aimone, L.D.; Robinson, C.; Chang, H.; Hudkins, R.L. Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(20), 5368-5372.
[http://dx.doi.org/10.1016/j.bmcl.2006.07.066] [PMID: 16890434]
[111]
Underiner, T.L.; Ruggeri, B.; Aimone, L.; Albom, M.; Angeles, T.; Chang, H.; Hudkins, R.L.; Hunter, K.; Josef, K.; Robinson, C.; Weinberg, L.; Yang, S.; Zulli, A. TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs. Bioorg. Med. Chem. Lett., 2008, 18(7), 2368-2372.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.069] [PMID: 18343109]
[112]
Dandu, R.; Zulli, A.L.; Bacon, E.R.; Underiner, T.; Robinson, C.; Chang, H.; Miknyoczki, S.; Grobelny, J.; Ruggeri, B.A.; Yang, S.; Albom, M.S.; Angeles, T.S.; Aimone, L.D.; Hudkins, R.L. Design and synthesis of dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases. Bioorg. Med. Chem. Lett., 2008, 18(6), 1916-1921.
[http://dx.doi.org/10.1016/j.bmcl.2008.02.001] [PMID: 18308565]
[113]
Ma, H.; Nguyen, B.; Li, L.; Greenblatt, S.; Williams, A.; Zhao, M.; Levis, M.; Rudek, M.; Duffield, A.; Small, D. TTT-3002 is a novel FLT3 tyrosine kinase inhibitor with activity against FLT3-associated leukemias in vitro and in vivo. Blood, 2014, 123(10), 1525-1534.
[http://dx.doi.org/10.1182/blood-2013-08-523035] [PMID: 24408321]
[114]
Jiang, X.; Zhou, J.; Ai, J.; Song, Z.; Peng, X.; Xing, L.; Xi, Y.; Guo, J.; Yao, Q.; Ding, J.; Geng, M.; Zhang, A. Novel tetracyclic benzo[b]carbazolones as highly potent and orally bioavailable ALK inhibitors: design, synthesis, and structure-activity relationship study. Eur. J. Med. Chem., 2015, 105, 39-56.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.005] [PMID: 26476749]
[115]
Organization, W.H. Global Health Observatory., www.who.int/gho/database/en/
[116]
Gross, S.; Rahal, R.; Stransky, N.; Lengauer, C.; Hoeflich, K.P. Targeting cancer with kinase inhibitors. J. Clin. Invest., 2015, 125(5), 1780-1789.
[http://dx.doi.org/10.1172/JCI76094] [PMID: 25932675]
[117]
Shchemelinin, I.; Sefc, L.; Necas, E. Protein kinases, their function and implication in cancer and other diseases. Folia Biol. (Praha), 2006, 52(3), 81-100.
[PMID: 17089919]
[118]
Chen, X.W.; Sun, J.; Zhou, S.F. Protein Kinase Inhibitors for Clinical Targeted Cancer Treatment. Clin. Pharmacol. Biopharm., 2013, 2(1), 1000-1112.
[http://dx.doi.org/10.4172/2167-065X.1000e112]
[119]
Sinha, S.; Pal, B.C.; Jagadeesh, S.; Banerjee, P.P.; Bandyopadhaya, A.; Bhattacharya, S. Mahanine inhibits growth and induces apoptosis in prostate cancer cells through the deactivation of Akt and activation of caspases. Prostate, 2006, 66(12), 1257-1265.
[http://dx.doi.org/10.1002/pros.20415] [PMID: 16683271]
[120]
Chatterjee, P.; Seal, S.; Mukherjee, S.; Kundu, R.; Bhuyan, M.; Barua, N.C.; Baruah, P.K.; Babu, S.P.; Bhattacharya, S. A carbazole alkaloid deactivates mTOR through the suppression of rictor and that induces apoptosis in lung cancer cells. Mol. Cell. Biochem., 2015, 405(1-2), 149-158.
[http://dx.doi.org/10.1007/s11010-015-2406-2] [PMID: 25893736]
[121]
Liu, Q.; Batt, D.G.; Lippy, J.S.; Surti, N.; Tebben, A.J.; Muckelbauer, J.K.; Chen, L.; An, Y.; Chang, C.; Pokross, M.; Yang, Z.; Wang, H.; Burke, J.R.; Carter, P.H.; Tino, J.A. Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton’s tyrosine kinase (BTK) and Janus kinase 2 (JAK2). Bioorg. Med. Chem. Lett., 2015, 25(19), 4265-4269.
[http://dx.doi.org/10.1016/j.bmcl.2015.07.102] [PMID: 26320619]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version1.05sRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[18:22:08] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[18:22:08] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[18:22:08] LOG.warning: strip_tags(): Passing null to parameter #1 ($string) of type string is depre...
  • warninglog[18:22:08] LOG.warning: strip_tags(): Passing null to parameter #1 ($string) of type string is depre...
  • warninglog[18:22:08] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (267ms)time
  • Application (784ms)time
  • 1 x Application (74.61%)
    784ms
    1 x Booting (25.38%)
    267ms
    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 duplicated567ms
    • 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 ('51368230','',1,1740421328,1740421328) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1740421328
      11.19msalphaeurekaselec_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 ('51368230','/article/103739',1,1740421328,1740421328)
      320μsalphaeurekaselec_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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) 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 >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 51368230 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 51368230) limit 1
      45.39msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 51368230
      • 1: 51368230
      • 2: 51368230
      • 3: 51368230
      • 4: 51368230
      • 5: 51368230
      • 6: 51368230
      • 7: 51368230
      • 8: 51368230
      • 9: 51368230
      • 10: 51368230
      • 11: 51368230
      • 12: 51368230
      • 13: 51368230
      • 14: 51368230
      • 15: 51368230
      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=103739
      30.1msalphaeurekaselec_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` = 56 limit 1
      8.23msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 56
      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=56) and sj.journal_id!=56 group by `j`.`nid`) as `aggregate_table`
      1.61msalphaeurekaselec_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=56) and sj.journal_id!=56 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.39msalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      63.82msalphaeurekaselec_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=56) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      1.92msalphaeurekaselec_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` = '103739'
      11.08msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 103739
      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` = '103739'
      17.5msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 103739
      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` = '103739' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      10.45msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 103739
      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
      350μsalphaeurekaselec_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
      690μsalphaeurekaselec_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 = 56 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      68.02msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      40.84msalphaeurekaselec_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 = 56 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      37.82msalphaeurekaselec_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` = 103739 limit 1
      370μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 103739
      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 = 103739 and content_type = 'article' order by status desc limit 1
      830μsalphaeurekaselec_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 = 298 and content_id!=103739 and cd.content_type = 'article' order by rand() limit 20
      194msalphaeurekaselec_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` = 178408 limit 1
      960μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 178408
      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
      360μsalphaeurekaselec_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` = 'MRMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      430μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: MRMC
      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 = '103739' 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) )
      540μsalphaeurekaselec_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 = '9694' 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) )
      450μsalphaeurekaselec_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 = '2708' 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) )
      410μsalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2708)
      6.57msalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9694) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9694) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9694)
      920μsalphaeurekaselec_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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 103739) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 103739) 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 <= 51368230 and j.to_ip >=51368230 )) and ((j.from_date <= 1740421328 and j.to_date >= 1740421328 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 103739)
      910μsalphaeurekaselec_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` < '444' and is_uploaded = 1 and issue_id = 9694 order by cast(first_page as SIGNED) desc limit 1
      710μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 444
      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` > '465' and is_uploaded = 1 and issue_id = 9694 order by cast(first_page as SIGNED) asc limit 1
      610μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 465
      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'
      230μsalphaeurekaselec_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
      300μsalphaeurekaselec_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` = 103739 limit 1
      3.76msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 103739
      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` = 56 and `b`.`banner_from_date` <= 1740421328 and `b`.`banner_to_date` >= 1740421328 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.89msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 56
      • 3: 1740421328
      • 4: 1740421328
      • 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` = 56 and `b`.`banner_from_date` <= 1740421328 and `b`.`banner_to_date` >= 1740421328 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: 56
      • 3: 1740421328
      • 4: 1740421328
      • 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='87b8b81a348eeee86429b05625d5a940'
      290μsalphaeurekaselec_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#?
        _token
        kRn7aVD2czLoFxjD6bj1Gci78lHK9UcBIIHCeUgj
        uc_cart_id
        87b8b81a348eeee86429b05625d5a940
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/103739" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/103739
        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:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IjZtYzRFdWhUbjhnbnBoY3c3czczTVE9PSIsInZhbHVlIjoiWkVYYVhhMFZ1eU1BeVBNdkZSZUZJNHliczdZYUEzNjlVZVpFSG1zcEpDOD0iLCJtYWMiOiJmODJiZDVkNjBmMTQ2NTU5ODljZjc5Njk0ZmI5Y2NiYzFmMjAxMjZiY2RjOThkMTYxMTU1MWE5YTRjODQwMDYxIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IjZtYzRFdWhUbjhnbnBoY3c3czczTVE9PSIsInZhbHVlIjoiWkVYYVhhMFZ1eU1BeVBNdkZSZUZJNHliczdZYUEzNjlVZVpFSG1zcEpDOD0iLCJtYWMiOiJmODJiZDVkNjBmMTQ2" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "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" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        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 => "Mon, 24 Feb 2025 18:22:08 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ikh2U1NmMUFJMSt0Ymhjd0RUckhQMFE9PSIsInZhbHVlIjoiSE1qd0orbkFvUnVNcU9KUWQvYzIxYWJSQTVBcUVaRktxcitFNm80NEtHMFo2NnRCRjdVOVNzeStUeXRETStkRTRBZWRRWXA0eU5OS0R0VzdnVTVsNm1YZFh2U1hvU2FsSzJUbktBcmRicnpsNk1QS2xMcDNlYTZzaVU2R2xSMnMiLCJtYWMiOiJlMzNiMmNhMTlkOGVhYTIyOTE4M2I3Mzk3MjUyMDU1YmNlYmM0ZThkZWQ5YzZjYTZhNTYxMzFiYWQ1MzFiNWRhIiwidGFnIjoiIn0%3D; expires=Thu, 27 Feb 2025 06:22:08 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Ikh2U1NmMUFJMSt0Ymhjd0RUckhQMFE9PSIsInZhbHVlIjoiSE1qd0orbkFvUnVNcU9KUWQvYzIxYWJSQTVBcUVaRktxcitFNm80NEtHMFo2NnRCRjdVOVNzeStUeXRETStkRTRBZWRRW" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjhndzRzS3h6UzZteXdSVDN3SmlSQ2c9PSIsInZhbHVlIjoiMHppUUIzMmxMcjdVRVk1NVUrMVNDR2dxRmV3NXFjaXVDbUhXRFRPK0FsQlc2Mkg0UWl4Y2dSOFZhNnBKZzFJMTZVVlVWSU45b29QeXNkUnE3d3NRSk9sUHNyVm1tYVhLcGhsQ1FQejdlbHBHYUZHV1NXY25raXlSUHlJZjFpWm4iLCJtYWMiOiJmZjgxNzgwMGM5OTE4MzVjODAyMDAxMWJiMDg1ZTQ4MDA1ZTQ5MmM4Mzg3M2U2MmYzZGQwMDkwNDYwYWQ0Y2NiIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IjhndzRzS3h6UzZteXdSVDN3SmlSQ2c9PSIsInZhbHVlIjoiMHppUUIzMmxMcjdVRVk1NVUrMVNDR2dxRmV3NXFjaXVDbUhXRFRPK0FsQlc2Mkg0UWl4Y2dSOFZ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ikh2U1NmMUFJMSt0Ymhjd0RUckhQMFE9PSIsInZhbHVlIjoiSE1qd0orbkFvUnVNcU9KUWQvYzIxYWJSQTVBcUVaRktxcitFNm80NEtHMFo2NnRCRjdVOVNzeStUeXRETStkRTRBZWRRWXA0eU5OS0R0VzdnVTVsNm1YZFh2U1hvU2FsSzJUbktBcmRicnpsNk1QS2xMcDNlYTZzaVU2R2xSMnMiLCJtYWMiOiJlMzNiMmNhMTlkOGVhYTIyOTE4M2I3Mzk3MjUyMDU1YmNlYmM0ZThkZWQ5YzZjYTZhNTYxMzFiYWQ1MzFiNWRhIiwidGFnIjoiIn0%3D; expires=Thu, 27-Feb-2025 06:22:08 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Ikh2U1NmMUFJMSt0Ymhjd0RUckhQMFE9PSIsInZhbHVlIjoiSE1qd0orbkFvUnVNcU9KUWQvYzIxYWJSQTVBcUVaRktxcitFNm80NEtHMFo2NnRCRjdVOVNzeStUeXRETStkRTRBZWRRW" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjhndzRzS3h6UzZteXdSVDN3SmlSQ2c9PSIsInZhbHVlIjoiMHppUUIzMmxMcjdVRVk1NVUrMVNDR2dxRmV3NXFjaXVDbUhXRFRPK0FsQlc2Mkg0UWl4Y2dSOFZhNnBKZzFJMTZVVlVWSU45b29QeXNkUnE3d3NRSk9sUHNyVm1tYVhLcGhsQ1FQejdlbHBHYUZHV1NXY25raXlSUHlJZjFpWm4iLCJtYWMiOiJmZjgxNzgwMGM5OTE4MzVjODAyMDAxMWJiMDg1ZTQ4MDA1ZTQ5MmM4Mzg3M2U2MmYzZGQwMDkwNDYwYWQ0Y2NiIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IjhndzRzS3h6UzZteXdSVDN3SmlSQ2c9PSIsInZhbHVlIjoiMHppUUIzMmxMcjdVRVk1NVUrMVNDR2dxRmV3NXFjaXVDbUhXRFRPK0FsQlc2Mkg0UWl4Y2dSOFZ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "kRn7aVD2czLoFxjD6bj1Gci78lHK9UcBIIHCeUgj" "uc_cart_id" => "87b8b81a348eeee86429b05625d5a940" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/103739" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-24 18:22:08GET/article/103739514371