Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways

Author(s): Giambattista Marotta, Filippo Basagni, Michela Rosini and Anna Minarini*

Volume 29, Issue 27, 2022

Published on: 12 January, 2022

Page: [4738 - 4755] Pages: 18

DOI: 10.2174/0929867329666211221153719

Price: $65

Abstract

Fyn kinase is a member of the Src non-receptor tyrosine kinase family. Fyn is involved in multiple signaling pathways extending from cell proliferation and differentiation to cell adhesion and cell motility, and it has been found to be overexpressed in various types of cancers. In the central nervous system, Fyn exerts several different functions such as axon–glial signal transduction, oligodendrocyte maturation, and myelination, and it is implicated in neuroinflammatory processes. Based on these premises, Fyn emerges as an attractive target in cancer and neurodegenerative disease therapy, particularly Alzheimer’s disease (AD), based on its activation by Aβ via cellular prion protein and its interaction with tau protein. However, Fyn is also a challenging target since the Fyn inhibitors discovered so far, due to the relevant homology of Fyn with other kinases, suffer from off-target effects. This review covers the efforts performed in the last decade to identify and optimize small molecules that effectively inhibit Fyn, both in enzymatic and in cell assays, including drug repositioning practices, as an opportunity for therapeutic intervention in neurodegeneration.

Keywords: Fyn kinase, neurodegeneration, dasatinib, tyrosine kinase, fyn inhibitors, pyrrolopyrimidine.

« Previous Next »
[1]
Boggon, T.J.; Eck, M.J. Structure and regulation of Src family kinases. Oncogene, 2004, 23(48), 7918-7927.
[http://dx.doi.org/10.1038/sj.onc.1208081] [PMID: 15489910]
[2]
Yang, K.; Belrose, J.; Trepanier, C.H.; Lei, G.; Jackson, M.F.; MacDonald, J.F. Fyn, a potential target for Alzheimer’s disease. J. Alzheimers Dis., 2011, 27(2), 243-252.
[http://dx.doi.org/10.3233/JAD-2011-110353] [PMID: 21799250]
[3]
Cooke, M.P.; Perlmutter, R.M. Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol., 1989, 1(1), 66-74.
[PMID: 2488273]
[4]
Matrone, C.; Petrillo, F.; Nasso, R.; Ferretti, G. Fyn tyrosine kinase as harmonizing factor in neuronal functions and dysfunctions. Int. J. Mol. Sci., 2020, 21(12), 4444.
[http://dx.doi.org/10.3390/ijms21124444] [PMID: 32580508]
[5]
Schenone, S.; Brullo, C.; Musumeci, F.; Biava, M.; Falchi, F.; Botta, M. Fyn kinase in brain diseases and cancer: The search for inhibitors. Curr. Med. Chem., 2011, 18(19), 2921-2942.
[http://dx.doi.org/10.2174/092986711796150531] [PMID: 21651487]
[6]
Yeatman, T.J. A renaissance for SRC. Nat. Rev. Cancer, 2004, 4(6), 470-480.
[http://dx.doi.org/10.1038/nrc1366] [PMID: 15170449]
[7]
Martellucci, S.; Clementi, L.; Sabetta, S.; Mattei, V.; Botta, L.; Angelucci, A. Src family kinases as therapeutic targets in advanced solid tumors: what we have learned so far. Cancers (Basel), 2020, 12(6), 1448.
[http://dx.doi.org/10.3390/cancers12061448] [PMID: 32498343]
[8]
Nygaard, H.B.; van Dyck, C.H.; Strittmatter, S.M. Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(1), 8.
[http://dx.doi.org/10.1186/alzrt238] [PMID: 24495408]
[9]
Yagi, T.; Shigetani, Y.; Okado, N.; Tokunaga, T.; Ikawa, Y.; Aizawa, S. Regional localization of Fyn in adult brain; studies with mice in which fyn gene was replaced by lacZ. Oncogene, 1993, 8(12), 3343-3351.
[PMID: 8247536]
[10]
Yagi, T.; Shigetani, Y.; Furuta, Y.; Nada, S.; Okado, N.; Ikawa, Y.; Aizawa, S. Fyn expression during early neurogenesis in mouse embryos. Oncogene, 1994, 9(9), 2433-2440.
[PMID: 8058305]
[11]
Umemori, H.; Wanaka, A.; Kato, H.; Takeuchi, M.; Tohyama, M.; Yamamoto, T. Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system. Brain Res. Mol. Brain Res., 1992, 16(3-4), 303-310.
[http://dx.doi.org/10.1016/0169-328X(92)90239-8] [PMID: 1337939]
[12]
Sperber, B.R.; Boyle-Walsh, E.A.; Engleka, M.J.; Gadue, P.; Peterson, A.C.; Stein, P.L.; Scherer, S.S.; McMorris, F.A. A unique role for Fyn in CNS myelination. J. Neurosci., 2001, 21(6), 2039-2047.
[http://dx.doi.org/10.1523/JNEUROSCI.21-06-02039.2001] [PMID: 11245687]
[13]
Baer, A.S.; Syed, Y.A.; Kang, S.U.; Mitteregger, D.; Vig, R.; Ffrench-Constant, C.; Franklin, R.J.; Altmann, F.; Lubec, G.; Kotter, M.R. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain, 2009, 132(Pt 2), 465-481.
[http://dx.doi.org/10.1093/brain/awn334] [PMID: 19208690]
[14]
Ohnishi, H.; Murata, Y.; Okazawa, H.; Matozaki, T. Src family kinases: modulators of neurotransmitter receptor function and behavior. Trends Neurosci., 2011, 34(12), 629-637.
[http://dx.doi.org/10.1016/j.tins.2011.09.005] [PMID: 22051158]
[15]
Trepanier, C.H.; Jackson, M.F.; MacDonald, J.F. Regulation of NMDA receptors by the tyrosine kinase Fyn. FEBS J., 2012, 279(1), 12-19.
[http://dx.doi.org/10.1111/j.1742-4658.2011.08391.x] [PMID: 21985328]
[16]
Osterhout, D.J.; Wolven, A.; Wolf, R.M.; Resh, M.D.; Chao, M.V. Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J. Cell Biol., 1999, 145(6), 1209-1218.
[http://dx.doi.org/10.1083/jcb.145.6.1209] [PMID: 10366594]
[17]
Shirazi, S.K.; Wood, J.G. The protein tyrosine kinase, fyn, in Alzheimer’s disease pathology. Neuroreport, 1993, 4(4), 435-437.
[http://dx.doi.org/10.1097/00001756-199304000-00024] [PMID: 8388744]
[18]
Ittner, L.M.; Ke, Y.D.; Delerue, F.; Bi, M.; Gladbach, A.; van Eersel, J.; Wölfing, H.; Chieng, B.C.; Christie, M.J.; Napier, I.A.; Eckert, A.; Staufenbiel, M.; Hardeman, E.; Götz, J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell, 2010, 142(3), 387-397.
[http://dx.doi.org/10.1016/j.cell.2010.06.036] [PMID: 20655099]
[19]
Briner, A.; Götz, J.; Polanco, J.C. Fyn kinase controls tau aggregation in vivo. Cell Rep., 2020, 32(7), 108045.
[http://dx.doi.org/10.1016/j.celrep.2020.108045] [PMID: 32814048]
[20]
Bamberger, M.E.; Harris, M.E.; McDonald, D.R.; Husemann, J.; Landreth, G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci., 2003, 23(7), 2665-2674.
[http://dx.doi.org/10.1523/JNEUROSCI.23-07-02665.2003] [PMID: 12684452]
[21]
Bernstein, S.L.; Dupuis, N.F.; Lazo, N.D.; Wyttenbach, T.; Condron, M.M.; Bitan, G.; Teplow, D.B.; Shea, J.E.; Ruotolo, B.T.; Robinson, C.V.; Bowers, M.T. Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease. Nat. Chem., 2009, 1(4), 326-331.
[http://dx.doi.org/10.1038/nchem.247] [PMID: 20703363]
[22]
Laurén, J.; Gimbel, D.A.; Nygaard, H.B.; Gilbert, J.W.; Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature, 2009, 457(7233), 1128-1132.
[http://dx.doi.org/10.1038/nature07761] [PMID: 19242475]
[23]
Lambert, M.P.; Barlow, A.K.; Chromy, B.A.; Edwards, C.; Freed, R.; Liosatos, M.; Morgan, T.E.; Rozovsky, I.; Trommer, B.; Viola, K.L.; Wals, P.; Zhang, C.; Finch, C.E.; Krafft, G.A.; Klein, W.L. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA, 1998, 95(11), 6448-6453.
[http://dx.doi.org/10.1073/pnas.95.11.6448] [PMID: 9600986]
[24]
Chin, J.; Palop, J.J.; Yu, G.Q.; Kojima, N.; Masliah, E.; Mucke, L. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J. Neurosci., 2004, 24(19), 4692-4697.
[http://dx.doi.org/10.1523/JNEUROSCI.0277-04.2004] [PMID: 15140940]
[25]
Iannuzzi, F.; Sirabella, R.; Canu, N.; Maier, T.J.; Annunziato, L.; Matrone, C. Fyn tyrosine kinase elicits amyloid precursor protein tyr682 phosphorylation in neurons from alzheimer’s disease patients. Cells, 2020, 9(8), 1807.
[http://dx.doi.org/10.3390/cells9081807] [PMID: 32751526]
[26]
Haass, C.; Mandelkow, E. Fyn-tau-amyloid: a toxic triad. Cell, 2010, 142(3), 356-358.
[http://dx.doi.org/10.1016/j.cell.2010.07.032] [PMID: 20691893]
[27]
Um, J.W.; Nygaard, H.B.; Heiss, J.K.; Kostylev, M.A.; Stagi, M.; Vortmeyer, A.; Wisniewski, T.; Gunther, E.C.; Strittmatter, S.M. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci., 2012, 15(9), 1227-1235.
[http://dx.doi.org/10.1038/nn.3178] [PMID: 22820466]
[28]
Angelopoulou, E.; Paudel, Y.N.; Julian, T.; Shaikh, M.F.; Piperi, C. Pivotal role of fyn kinase in Parkinson’s disease and levodopa-induced dyskinesia: a novel therapeutic target? Mol. Neurobiol., 2021, 58(4), 1372-1391.
[http://dx.doi.org/10.1007/s12035-020-02201-z] [PMID: 33175322]
[29]
Sharma, S.; Carlson, S.; Puttachary, S.; Sarkar, S.; Showman, L.; Putra, M.; Kanthasamy, A.G.; Thippeswamy, T. Role of the Fyn-PKCδ signaling in SE-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy. Neurobiol. Dis., 2018, 110, 102-121.
[http://dx.doi.org/10.1016/j.nbd.2017.11.008] [PMID: 29197620]
[30]
Panicker, N.; Saminathan, H.; Jin, H.; Neal, M.; Harischandra, D.S.; Gordon, R.; Kanthasamy, K.; Lawana, V.; Sarkar, S.; Luo, J.; Anantharam, V.; Kanthasamy, A.G.; Kanthasamy, A. Fyn kinase regulates microglial neuroinflammatory responses in cell culture and animal models of Parkinson’s disease. J. Neurosci., 2015, 35(27), 10058-10077.
[http://dx.doi.org/10.1523/JNEUROSCI.0302-15.2015] [PMID: 26157004]
[31]
Mkaddem, S.B.; Murua, A.; Flament, H.; Titeca-Beauport, D.; Bounaix, C.; Danelli, L.; Launay, P.; Benhamou, M.; Blank, U.; Daugas, E.; Charles, N.; Monteiro, R.C. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nat. Commun., 2017, 8(1), 246.
[http://dx.doi.org/10.1038/s41467-017-00294-0] [PMID: 28811476]
[32]
Lee, C.; Low, C.Y.; Francis, P.T.; Attems, J.; Wong, P.T.; Lai, M.K.; Tan, M.G. An isoform-specific role of FynT tyrosine kinase in Alzheimer’s disease. J. Neurochem., 2016, 136(3), 637-650.
[http://dx.doi.org/10.1111/jnc.13429] [PMID: 26561212]
[33]
Lee, C.; Low, C.Y.; Wong, S.Y.; Lai, M.K.; Tan, M.G. Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes. Sci. Rep., 2017, 7, 43651.
[http://dx.doi.org/10.1038/srep43651] [PMID: 28266558]
[34]
Tang, S.J.; Fesharaki-Zadeh, A.; Takahashi, H.; Nies, S.H.; Smith, L.M.; Luo, A.; Chyung, A.; Chiasseu, M.; Strittmatter, S.M. Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy. Acta Neuropathol. Commun., 2020, 8(1), 96.
[http://dx.doi.org/10.1186/s40478-020-00976-9] [PMID: 32611392]
[35]
Kaufman, A.C.; Salazar, S.V.; Haas, L.T.; Yang, J.; Kostylev, M.A.; Jeng, A.T.; Robinson, S.A.; Gunther, E.C.; van Dyck, C.H.; Nygaard, H.B.; Strittmatter, S.M. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann. Neurol., 2015, 77(6), 953-971.
[http://dx.doi.org/10.1002/ana.24394] [PMID: 25707991]
[36]
Chakraborty, S.; Inukai, T.; Fang, L.; Golkowski, M.; Maly, D.J. Targeting dynamic atp-binding site features allows discrimination between highly homologous protein kinases. ACS Chem. Biol., 2019, 14(6), 1249-1259.
[http://dx.doi.org/10.1021/acschembio.9b00214] [PMID: 31038916]
[37]
Williams, J.C.; Wierenga, R.K.; Saraste, M. Insights into Src kinase functions: structural comparisons. Trends Biochem. Sci., 1998, 23(5), 179-184.
[http://dx.doi.org/10.1016/S0968-0004(98)01202-X] [PMID: 9612082]
[38]
Kinoshita, T.; Matsubara, M.; Ishiguro, H.; Okita, K.; Tada, T. Structure of human Fyn kinase domain complexed with staurosporine. Biochem. Biophys. Res. Commun., 2006, 346(3), 840-844.
[http://dx.doi.org/10.1016/j.bbrc.2006.05.212] [PMID: 16782058]
[39]
Rachman, M.; Bajusz, D.; Hetényi, A.; Scarpino, A.; Merő, B.; Egyed, A.; Buday, L.; Barril, X.; Keserű, G.M. Discovery of a novel kinase hinge binder fragment by dynamic undocking. RSC Med. Chem., 2020, 11(5), 552-558.
[http://dx.doi.org/10.1039/C9MD00519F] [PMID: 33479656]
[40]
Nygaard, H.B. Targeting fyn kinase in Alzheimer’s disease. Biol. Psychiatry, 2018, 83(4), 369-376.
[http://dx.doi.org/10.1016/j.biopsych.2017.06.004] [PMID: 28709498]
[41]
Hennequin, L.F.; Allen, J.; Breed, J.; Curwen, J.; Fennell, M.; Green, T.P.; Lambert-van der Brempt, C.; Morgentin, R.; Norman, R.A.; Olivier, A.; Otterbein, L.; Plé, P.A.; Warin, N.; Costello, G.N. -(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem., 2006, 49(22), 6465-6488.
[http://dx.doi.org/10.1021/jm060434q] [PMID: 17064066]
[42]
Fagiani, F.; Lanni, C.; Racchi, M.; Govoni, S. Targeting dementias through cancer kinases inhibition. Alzheimers Dement. (N. Y.), 2020, 6(1), e12044.
[http://dx.doi.org/10.1002/trc2.12044] [PMID: 32671184]
[43]
Nygaard, H.B.; Wagner, A.F.; Bowen, G.S.; Good, S.P.; MacAvoy, M.G.; Strittmatter, K.A.; Kaufman, A.C.; Rosenberg, B.J.; Sekine-Konno, T.; Varma, P.; Chen, K.; Koleske, A.J.; Reiman, E.M.; Strittmatter, S.M.; van Dyck, C.H. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer’s disease. Alzheimers Res. Ther., 2015, 7(1), 35.
[http://dx.doi.org/10.1186/s13195-015-0119-0] [PMID: 25874001]
[44]
van Dyck, C.H.; Nygaard, H.B.; Chen, K.; Donohue, M.C.; Raman, R.; Rissman, R.A.; Brewer, J.B.; Koeppe, R.A.; Chow, T.W.; Rafii, M.S.; Gessert, D.; Choi, J.; Turner, R.S.; Kaye, J.A.; Gale, S.A.; Reiman, E.M.; Aisen, P.S.; Strittmatter, S.M. Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurol., 2019, 76(10), 1219-1229.
[http://dx.doi.org/10.1001/jamaneurol.2019.2050] [PMID: 31329216]
[45]
Hahn, K.A.; Ogilvie, G.; Rusk, T.; Devauchelle, P.; Leblanc, A.; Legendre, A.; Powers, B.; Leventhal, P.S.; Kinet, J.P.; Palmerini, F.; Dubreuil, P.; Moussy, A.; Hermine, O.; Hermine, O. Masitinib is safe and effective for the treatment of canine mast cell tumors. J. Vet. Intern. Med., 2008, 22(6), 1301-1309.
[http://dx.doi.org/10.1111/j.1939-1676.2008.0190.x] [PMID: 18823406]
[46]
Folch, J.; Petrov, D.; Ettcheto, M.; Pedrós, I.; Abad, S.; Beas-Zarate, C.; Lazarowski, A.; Marin, M.; Olloquequi, J.; Auladell, C.; Camins, A. Masitinib for the treatment of mild to moderate Alzheimer’s disease. Expert Rev. Neurother., 2015, 15(6), 587-596.
[http://dx.doi.org/10.1586/14737175.2015.1045419] [PMID: 25961655]
[47]
Piette, F.; Belmin, J.; Vincent, H.; Schmidt, N.; Pariel, S.; Verny, M.; Marquis, C.; Mely, J.; Hugonot-Diener, L.; Kinet, J.P.; Dubreuil, P.; Moussy, A.; Hermine, O. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res. Ther., 2011, 3(2), 16.
[http://dx.doi.org/10.1186/alzrt75] [PMID: 21504563]
[48]
Mora, J.S.; Genge, A.; Chio, A.; Estol, C.J.; Chaverri, D.; Hernández, M.; Marín, S.; Mascias, J.; Rodriguez, G.E.; Povedano, M.; Paipa, A.; Dominguez, R.; Gamez, J.; Salvado, M.; Lunetta, C.; Ballario, C.; Riva, N.; Mandrioli, J.; Moussy, A.; Kinet, J.P.; Auclair, C.; Dubreuil, P.; Arnold, V.; Mansfield, C.D.; Hermine, O. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph. Lateral Scler. Frontotemporal Degener., 2020, 21(1-2), 5-14.
[http://dx.doi.org/10.1080/21678421.2019.1632346] [PMID: 31280619]
[49]
Tokarski, J.S.; Newitt, J.A.; Chang, C.Y.; Cheng, J.D.; Wittekind, M.; Kiefer, S.E.; Kish, K.; Lee, F.Y.; Borzillerri, R.; Lombardo, L.J.; Xie, D.; Zhang, Y.; Klei, H.E. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res., 2006, 66(11), 5790-5797.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4187] [PMID: 16740718]
[50]
Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R.V.; Shen, Z.; Cook, L.S.; Doweyko, A.M.; Pitt, S.; Pang, S.; Shen, D.R.; Fang, Q.; de Fex, H.F.; McIntyre, K.W.; Shuster, D.J.; Gillooly, K.M.; Behnia, K.; Schieven, G.L.; Wityak, J.; Barrish, J.C. 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J. Med. Chem., 2006, 49(23), 6819-6832.
[http://dx.doi.org/10.1021/jm060727j] [PMID: 17154512]
[51]
Dhawan, G.; Combs, C.K. Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer’s disease. J. Neuroinflammation, 2012, 9, 117.
[http://dx.doi.org/10.1186/1742-2094-9-117] [PMID: 22673542]
[52]
Zhang, P.; Kishimoto, Y.; Grammatikakis, I.; Gottimukkala, K.; Cutler, R.G.; Zhang, S.; Abdelmohsen, K.; Bohr, V.A.; Misra Sen, J.; Gorospe, M.; Mattson, M.P. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci., 2019, 22(5), 719-728.
[http://dx.doi.org/10.1038/s41593-019-0372-9] [PMID: 30936558]
[53]
Hanke, J.H.; Gardner, J.P.; Dow, R.L.; Changelian, P.S.; Brissette, W.H.; Weringer, E.J.; Pollok, B.A.; Connelly, P.A. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J. Biol. Chem., 1996, 271(2), 695-701.
[http://dx.doi.org/10.1074/jbc.271.2.695] [PMID: 8557675]
[54]
Abdellatif, K.R.A.; Bakr, R.B. Pyridine and fused pyrimidine derivatives as promising protein kinase inhibitors for cancer treatment. Med. Chem. Res., 2021, 30, 31-49.
[http://dx.doi.org/10.1007/s00044-020-02656-8]
[55]
Shim, H.J.; Kim, H.I.; Lee, S.T. The associated pyrazolopyrimidines PP1 and PP2 inhibit protein tyrosine kinase 6 activity and suppress breast cancer cell proliferation. Oncol. Lett., 2017, 13(3), 1463-1469.
[http://dx.doi.org/10.3892/ol.2017.5564] [PMID: 28454278]
[56]
Lau, W.C. Methods, compositions and uses of novel Fyn kinase inhibitors, US Patent 10,688,093B2, 2017.
[57]
Tintori, C.; La Sala, G.; Vignaroli, G.; Botta, L.; Fallacara, A.L.; Falchi, F.; Radi, M.; Zamperini, C.; Dreassi, E.; Dello Iacono, L.; Orioli, D.; Biamonti, G.; Garbelli, M.; Lossani, A.; Gasparrini, F.; Tuccinardi, T.; Laurenzana, I.; Angelucci, A.; Maga, G.; Schenone, S.; Brullo, C.; Musumeci, F.; Desogus, A.; Crespan, E.; Botta, M. Studies on the atp binding site of fyn kinase for the identification of new inhibitors and their evaluation as potential agents against tauopathies and tumors. J. Med. Chem., 2015, 58(11), 4590-4609.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00140] [PMID: 25923950]
[58]
Musumeci, F.; Sanna, M.; Grossi, G.; Brullo, C.; Fallacara, A.L.; Schenone, S. Pyrrolo[2,3-d]pyrimidines as kinase inhibitors. Curr. Med. Chem., 2017, 24(19), 2059-2085.
[http://dx.doi.org/10.2174/0929867324666170303162100] [PMID: 28266267]
[59]
Dincer, S.; Cetin, K.T.; Onay-Besikci, A.; Ölgen, S. Synthesis, biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors. J. Enzyme Inhib. Med. Chem., 2013, 28(5), 1080-1087.
[http://dx.doi.org/10.3109/14756366.2012.715288] [PMID: 22957720]
[60]
Prakash, C.R.; Raja, S. Indolinones as promising scaffold as kinase inhibitors: a review. Mini Rev. Med. Chem., 2012, 12(2), 98-119.
[http://dx.doi.org/10.2174/138955712798995039] [PMID: 22372601]
[61]
Guan, H.; Laird, A.D.; Blake, R.A.; Tang, C.; Liang, C. Design and synthesis of aminopropyl tetrahydroindole-based indolin-2-ones as selective and potent inhibitors of Src and Yes tyrosine kinase. Bioorg. Med. Chem. Lett., 2004, 14(1), 187-190.
[http://dx.doi.org/10.1016/j.bmcl.2003.09.069] [PMID: 14684325]
[62]
Kurt, K.Z.; Aydin, D.; Isgor, Y.G.; Isgor, B.S.; Olgen, S. Synthesis and biological study of novel indole-3-imine-2-on derivatives as src kinase and glutathione s-transferase inhibitors. Lett. Drug Des. Discov., 2013, 10, 19-26.
[http://dx.doi.org/10.2174/157018013804142456]
[63]
Olgen, S.; Akaho, E.; Nebioglu, D. Evaluation of indole esters as inhibitors of p60(c-Src) receptor tyrosine kinase and investigation of the inhibition using receptor docking studies. J. Enzyme Inhib. Med. Chem., 2003, 18(6), 485-490.
[http://dx.doi.org/10.1080/14756360310001612211] [PMID: 15008512]
[64]
Kiliç, Z.; Isgör, Y.G.; Olgen, S. Synthesis and pp60c-Src tyrosine kinase inhibitory activities of novel indole-3-imine and amine derivatives substituted at N1 and C5. Arch. Pharm. (Weinheim), 2009, 342(6), 333-343.
[http://dx.doi.org/10.1002/ardp.200800216] [PMID: 19475593]
[65]
Kilic-Kurt, Z.; Onay-Besikci, A.; Ölgen, S. Synthesis, biological and computational evaluation of novel oxindole derivatives as inhibitors of src family kinases. Lett. Drug Des. Discov., 2013, 10, 713-718.
[http://dx.doi.org/10.2174/15701808113109070023]
[66]
Schade, N.; Koch, P.; Ansideri, F.; Krystof, V.; Holzer, M.; Hilgeroth, A. Evaluation of novel substituted furopyridines as inhibitors of protein kinases related to tau pathology in Alzheimer´s disease. Med. Chem., 2021, 17(8), 844-855.
[http://dx.doi.org/10.2174/1573406417666210601144510] [PMID: 34061007]
[67]
Jha, V.; Macchia, M.; Tuccinardi, T.; Poli, G. Three-dimensional interactions analysis of the anticancer target c-src kinase with its inhibitors. Cancers (Basel), 2020, 12(8), 2327.
[http://dx.doi.org/10.3390/cancers12082327] [PMID: 32824733]
[68]
Francini, C.M.; Fallacara, A.L.; Artusi, R.; Mennuni, L.; Calgani, A.; Angelucci, A.; Schenone, S.; Botta, M. Identification of aminoimidazole and aminothiazole derivatives as SRC family kinase inhibitors. ChemMedChem, 2015, 10(12), 2027-2041.
[http://dx.doi.org/10.1002/cmdc.201500428] [PMID: 26514807]
[69]
Francini, C.M.; Musumeci, F.; Fallacara, A.L.; Botta, L.; Molinari, A.; Artusi, R.; Mennuni, L.; Angelucci, A.; Schenone, S. Optimization of aminoimidazole derivatives as Src family kinase inhibitors. Molecules, 2018, 23(9), 2369.
[http://dx.doi.org/10.3390/molecules23092369] [PMID: 30227617]
[70]
Lee, C.G.; Koo, J.H.; Kim, S.G. Phytochemical regulation of Fyn and AMPK signaling circuitry. Arch. Pharm. Res., 2015, 38(12), 2093-2105.
[http://dx.doi.org/10.1007/s12272-015-0611-x] [PMID: 25951818]
[71]
Luo, C.; Zou, L.; Sun, H.; Peng, J.; Gao, C.; Bao, L.; Ji, R.; Jin, Y.; Sun, S. A review of the anti-inflammatory effects of rosmarinic acid on inflammatory diseases. Front. Pharmacol., 2020, 11, 153.
[http://dx.doi.org/10.3389/fphar.2020.00153] [PMID: 32184728]
[72]
Rocha, J.; Eduardo-Figueira, M.; Barateiro, A.; Fernandes, A.; Brites, D.; Bronze, R.; Duarte, C.M.; Serra, A.T.; Pinto, R.; Freitas, M.; Fernandes, E.; Silva-Lima, B.; Mota-Filipe, H.; Sepodes, B. Anti-inflammatory effect of rosmarinic acid and an extract of Rosmarinus officinalis in rat models of local and systemic inflammation. Basic Clin. Pharmacol. Toxicol., 2015, 116(5), 398-413.
[http://dx.doi.org/10.1111/bcpt.12335] [PMID: 25287116]
[73]
Jelić, D.; Mildner, B.; Kostrun, S.; Nujić, K.; Verbanac, D.; Culić, O.; Antolović, R.; Brandt, W. Homology modeling of human Fyn kinase structure: discovery of rosmarinic acid as a new Fyn kinase inhibitor and in silico study of its possible binding modes. J. Med. Chem., 2007, 50(6), 1090-1100.
[http://dx.doi.org/10.1021/jm0607202] [PMID: 17315853]
[74]
Rong, H.; Liang, Y.; Niu, Y. Rosmarinic acid attenuates β-amyloid-induced oxidative stress via Akt/GSK-3β/Fyn-mediated Nrf2 activation in PC12 cells. Free Radic. Biol. Med., 2018, 120, 114-123.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.03.028] [PMID: 29555592]
[75]
Han, Y.; Ma, L.; Zhao, L.; Feng, W.; Zheng, X. Rosmarinic inhibits cell proliferation, invasion and migration via up-regulating miR-506 and suppressing MMP2/16 expression in pancreatic cancer. Biomed. Pharmacother., 2019, 115, 108878.
[http://dx.doi.org/10.1016/j.biopha.2019.108878] [PMID: 31060006]
[76]
Herman, F.; Westfall, S.; Brathwaite, J.; Pasinetti, G.M. Suppression of presymptomatic oxidative stress and inflammation in neurodegeneration by grape-derived polyphenols. Front. Pharmacol., 2018, 9, 867.
[http://dx.doi.org/10.3389/fphar.2018.00867] [PMID: 30210334]
[77]
Di Meo, F.; Valentino, A.; Petillo, O.; Peluso, G.; Filosa, S.; Crispi, S. Bioactive polyphenols and neuromodulation: molecular mechanisms in neurodegeneration. Int. J. Mol. Sci., 2020, 21(7), 2564.
[http://dx.doi.org/10.3390/ijms21072564] [PMID: 32272735]
[78]
de Matos, A.M.; de Macedo, M.P.; Rauter, A.P. Bridging type 2 diabetes and Alzheimer’s disease: assembling the puzzle pieces in the quest for the molecules with therapeutic and preventive potential. Med. Res. Rev., 2018, 38(1), 261-324.
[http://dx.doi.org/10.1002/med.21440] [PMID: 28422298]
[79]
de Matos, A.M.; Blázquez-Sánchez, M.T.; Bento-Oliveira, A.; de Almeida, R.F.M.; Nunes, R.; Lopes, P.E.M.; Machuqueiro, M.; Cristóvão, J.S.; Gomes, C.M.; Souza, C.S.; El Idrissi, I.G.; Colabufo, N.A.; Diniz, A.; Marcelo, F.; Oliveira, M.C.; López, Ó.; Fernandez-Bolaños, J.G.; Dätwyler, P.; Ernst, B.; Ning, K.; Garwood, C.; Chen, B.; Rauter, A.P. Glucosylpolyphenols as inhibitors of aβ-induced fyn kinase activation and tau phosphorylation: synthesis, membrane permeability, and exploratory target assessment within the scope of type 2 diabetes and Alzheimer’s disease. J. Med. Chem., 2020, 63(20), 11663-11690.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00841] [PMID: 32959649]
[80]
Jesus, A.R.; Dias, C.; Matos, A.M.; de Almeida, R.F.; Viana, A.S.; Marcelo, F.; Ribeiro, R.T.; Macedo, M.P.; Airoldi, C.; Nicotra, F.; Martins, A.; Cabrita, E.J.; Jiménez-Barbero, J.; Rauter, A.P. Exploiting the therapeutic potential of 8-β-d-glucopyranosylgenistein: synthesis, antidiabetic activity, and molecular interaction with islet amyloid polypeptide and amyloid β-peptide (1-42). J. Med. Chem., 2014, 57(22), 9463-9472.
[http://dx.doi.org/10.1021/jm501069h] [PMID: 25347820]
[81]
Rawat, P.; Kumar, M.; Rahuja, N.; Lal Srivastava, D.S.; Srivastava, A.K.; Maurya, R. Synthesis and antihyperglycemic activity of phenolic C-glycosides. Bioorg. Med. Chem. Lett., 2011, 21(1), 228-233.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.031] [PMID: 21129962]
[82]
He, L.; Zhang, Y.Z.; Tanoh, M.; Chen, G-R.; Praly, J-P.; Chrysina, D.E.; Tiraidis, C.; Kosmopoulou, M.; Leonidas, D.D.; Oikonomakos, G.N. In the search of glycogen phosphorylase inhibitors: synthesis of c‐ d ‐glycopyranosyl-benzo(hydro)quinones – inhibition of and binding to glycogen phosphorylase in the crystal. Eur. J. Med. Chem., 2007, 2007(4), 596-606.
[83]
Kim, A.Y.; Lee, C.G.; Lee, D.Y.; Li, H.; Jeon, R.; Ryu, J.H.; Kim, S.G. Enhanced antioxidant effect of prenylated polyphenols as Fyn inhibitor. Free Radic. Biol. Med., 2012, 53(5), 1198-1208.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.06.039] [PMID: 22771471]
[84]
Yazaki, K.; Sasaki, K.; Tsurumaru, Y. Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry, 2009, 70(15-16), 1739-1745.
[http://dx.doi.org/10.1016/j.phytochem.2009.08.023] [PMID: 19819506]
[85]
Arthur, G.; Oliver, W.; Klaus, B.; Thomas, S.; Gökhan, I.; Sharon, B.; Isabelle, T.; Pierre, D.; Thierry, L. Hierarchical graph representation of pharmacophore models. Front. Mol. Biosci., 2020, 7, 599059.
[http://dx.doi.org/10.3389/fmolb.2020.599059] [PMID: 33425991]
[86]
Seidel, T.; Wieder, O.; Garon, A.; Langer, T. Applications of the pharmacophore concept in natural product inspired drug design. Mol. Inform., 2020, 39(11), e2000059.
[http://dx.doi.org/10.1002/minf.202000059] [PMID: 32578959]
[87]
Qing, X.; Lee, X.Y.; De Raeymaecker, J.; Tame, J.; Zhang, K.; De Maeyer, M.; Voet, A. Pharmacophore modeling: Advances, limitations, and current utility in drug discovery. J. Receptor Ligand Channel Res., 2014, 7, 81-92.
[88]
Baroni, M.; Cruciani, G.; Sciabola, S.; Perruccio, F.; Mason, J.S. A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for Ligands and Proteins (FLAP): theory and application. J. Chem. Inf. Model., 2007, 47(2), 279-294.
[http://dx.doi.org/10.1021/ci600253e] [PMID: 17381166]
[89]
Ehrt, C.; Brinkjost, T.; Koch, O. Impact of binding site comparisons on medicinal chemistry and rational molecular design. J. Med. Chem., 2016, 59(9), 4121-4151.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00078] [PMID: 27046190]
[90]
Poli, G.; Tuccinardi, T.; Rizzolio, F.; Caligiuri, I.; Botta, L.; Granchi, C.; Ortore, G.; Minutolo, F.; Schenone, S.; Martinelli, A. Identification of new Fyn kinase inhibitors using a FLAP-based approach. J. Chem. Inf. Model., 2013, 53(10), 2538-2547.
[http://dx.doi.org/10.1021/ci4002553] [PMID: 24001328]
[91]
Xue, F.; Jia, Y.; Zhao, J. Overexpression of FYN suppresses the epithelial-to-mesenchymal transition through down-regulating PI3K/AKT pathway in lung adenocarcinoma. Surg. Oncol., 2020, 33, 108-117.
[http://dx.doi.org/10.1016/j.suronc.2020.02.002] [PMID: 32561075]
[92]
Xie, Y.G.; Yu, Y.; Hou, L.K.; Wang, X.; Zhang, B.; Cao, X.C. FYN promotes breast cancer progression through epithelial-mesenchymal transition. Oncol. Rep., 2016, 36(2), 1000-1006.
[http://dx.doi.org/10.3892/or.2016.4894] [PMID: 27349276]
[93]
Poli, G.; Lapillo, M.; Granchi, C.; Caciolla, J.; Mouawad, N.; Caligiuri, I.; Rizzolio, F.; Langer, T.; Minutolo, F.; Tuccinardi, T. Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 956-961.
[http://dx.doi.org/10.1080/14756366.2018.1469017] [PMID: 29747534]
[94]
Mukherjee, A.; Singh, R.; Udayan, S.; Biswas, S.; Reddy, P.P.; Manmadhan, S.; George, G.; Kumar, S.; Das, R.; Rao, B.M.; Gulyani, A. A Fyn biosensor reveals pulsatile, spatially localized kinase activity and signaling crosstalk in live mammalian cells. eLife, 2020, 9, 9.
[http://dx.doi.org/10.7554/eLife.50571] [PMID: 32017701]

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy