Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

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

Review Article

New Insights on Fak and Fak Inhibitors

Author(s): Chiara Brullo* and Bruno Tasso

Volume 28, Issue 17, 2021

Published on: 03 November, 2020

Page: [3318 - 3338] Pages: 21

DOI: 10.2174/0929867327666201103162239

Price: $65

conference banner
Abstract

Background: Focal adhesion kinase (Fak) is a cytoplasmic protein tyrosine kinase overexpressed and activated in different solid cancers; it has shown an important role in metastasis formation, cell migration, invasion and angiogenesis and consequently it has been proposed as a potential target in cancer therapy, particularly in a metastatic phase. In recent years, different investigations have highlighted the importance of new Fak inhibitors as potential anti-cancer drugs, but other studies evidenced its role in different pathologies related to the cardiac function or viral infection.

Methods: An extensive bibliographic research (104 references) has been done concerning the structure of Fak, its importance in tumor development, but also in other pathologies currently under study. The compounds currently subjected to clinical studies were therefore treated using the appropriate databases. Finally, the main chemical scaffolds currently under preclinical investigation were analyzed, focusing on their molecular structures and on the activity structure relationships (SAR).

Results: At the moment, only a few reversible ATP-competitive inhibitors are under investigation in pre-clinical studies and clinical trials. Other compounds, with different chemical scaffolds, are investigated to obtain more active and selective Fak inhibitors. This mini-review is a summary of different Fak functions in cancer and other pathologies; the compounds today in clinical trials and the recent chemical scaffolds (also included in patents) giving the most interesting results are investigated. In addition, PROTAC molecules are reported.

Conclusion: All reported results evidenced that additional studies are necessary to design and synthesize new selective and more active compounds, although promising information has been obtained from associations between Fak inhibitors and other different anti- cancer drugs. In addition, the other important roles evidenced, both at the nuclear level and in non-cancerous cells, make this protein an increasingly important target in pharmaceutical chemistry.

Keywords: Focal adhesion kinase, Fak inhibitors, metastasis, cancer therapy, clinical trials, PROTACS.

[1]
Schaller, M.D.; Parsons, J.T. Focal adhesion kinase: an integrin-linked protein tyrosine kinase. Trends Cell Biol., 1993, 3(8), 258-262.[http://dx.doi.org/10.1016/0962-8924(93)90053-4] [PMID: 14731743]
[2]
Schlaepfer, D.D.; Hanks, S.K.; Hunter, T.; van der Geer, P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature, 1994, 372(6508), 786-791.[http://dx.doi.org/10.1038/372786a0] [PMID: 7997267]
[3]
Schaller, M.D. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J. Cell Sci., 2010, 123(Pt 7), 1007-1013.[http://dx.doi.org/10.1242/jcs.045112] [PMID: 20332118]
[4]
Parsons, J.T.; Slack-Davis, J.; Tilghman, R.; Roberts, W.G. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin. Cancer Res., 2008, 14(3), 627-632.[http://dx.doi.org/10.1158/1078-0432.CCR-07-2220] [PMID: 18245520]
[5]
Shanthi, E.; Krishna, M.H.; Arunesh, G.M.; Venkateswara Reddy, K.; Sooriya Kumar, J.; Viswanadhan, V.N. Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review. Expert Opin. Ther. Pat., 2014, 24(10), 1077-1100.[http://dx.doi.org/10.1517/13543776.2014.948845] [PMID: 25113248]
[6]
Parsons, J.T. Focal adhesion kinase: the first ten years. J. Cell Sci., 2003, 116(Pt 8), 1409-1416.[http://dx.doi.org/10.1242/jcs.00373] [PMID: 12640026]
[7]
Guan, J.L.; Trevithick, J.E.; Hynes, R.O. Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein. Cell Regul., 1991, 2(11), 951-964.[http://dx.doi.org/10.1091/mbc.2.11.951] [PMID: 1725602]
[8]
Schwock, J.; Dhani, N.; Hedley, D.W. Targeting focal adhesion kinase signaling in tumor growth and metastasis. Expert Opin. Ther. Targets, 2010, 14(1), 77-94.[http://dx.doi.org/10.1517/14728220903460340] [PMID: 20001212]
[9]
Lv, P.C.; Jiang, A.Q.; Zhang, W.M.; Zhu, H.L. FAK inhibitors in Cancer, a patent review. Expert Opin. Ther. Pat., 2018, 28(2), 139-145.[http://dx.doi.org/10.1080/13543776.2018.1414183] [PMID: 29210300]
[10]
Cary, L.A.; Guan, J.L. Focal adhesion kinase in integrin-mediated signaling. Front. Biosci., 1999, 4(1-3)[http://dx.doi.org/10.2741/Cary] [PMID: 9889179]
[11]
Reiske, H.R.; Zhao, J.; Han, D.C.; Cooper, L.A.; Guan, J.L. Analysis of FAK-associated signaling pathways in the regulation of cell cycle progression. FEBS Lett., 2000, 486(3), 275-280.[http://dx.doi.org/10.1016/S0014-5793(00)02295-X] [PMID: 11119718]
[12]
McLean, G.W.; Carragher, N.O.; Avizienyte, E.; Evans, J.; Brunton, V.G.; Frame, M.C. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity. Nat. Rev. Cancer, 2005, 5(7), 505-515.[http://dx.doi.org/10.1038/nrc1647] [PMID: 16069815]
[13]
Golubovskaya, V.M.; Conway-Dorsey, K.; Edmiston, S.N.; Tse, C.K.; Lark, A.A.; Livasy, C.A.; Moore, D.; Millikan, R.C.; Cance, W.G. FAK overexpression and p53 mutations are highly correlated in human breast cancer. Int. J. Cancer, 2009, 125(7), 1735-1738.[http://dx.doi.org/10.1002/ijc.24486] [PMID: 19521985]
[14]
Lim, S.T.; Chen, X.L.; Lim, Y.; Hanson, D.A.; Vo, T.T.; Howerton, K.; Larocque, N.; Fisher, S.J.; Schlaepfer, D.D.; Ilic, D. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell, 2008, 29(1), 9-22.[http://dx.doi.org/10.1016/j.molcel.2007.11.031] [PMID: 18206965]
[15]
Sulzmaier, F.J.; Jean, C.; Schlaepfer, D.D. FAK in cancer: mechanistic findings and clinical applications. Nat. Rev. Cancer, 2014, 14(9), 598-610.[http://dx.doi.org/10.1038/nrc3792] [PMID: 25098269]
[16]
Goode, E.L.; Chenevix-Trench, G.; Song, H.; Ramus, S.J.; Notaridou, M.; Lawrenson, K.; Widschwendter, M.; Vierkant, R.A.; Larson, M.C.; Kjaer, S.K.; Birrer, M.J.; Berchuck, A.; Schildkraut, J.; Tomlinson, I.; Kiemeney, L.A.; Cook, L.S.; Gronwald, J.; Garcia-Closas, M.; Gore, M.E.; Campbell, I.; Whittemore, A.S.; Sutphen, R.; Phelan, C.; Anton-Culver, H.; Pearce, C.L.; Lambrechts, D.; Rossing, M.A.; Chang-Claude, J.; Moysich, K.B.; Goodman, M.T.; Dörk, T.; Nevanlinna, H.; Ness, R.B.; Rafnar, T.; Hogdall, C.; Hogdall, E.; Fridley, B.L.; Cunningham, J.M.; Sieh, W.; McGuire, V.; Godwin, A.K.; Cramer, D.W.; Hernandez, D.; Levine, D.; Lu, K.; Iversen, E.S.; Palmieri, R.T.; Houlston, R.; van Altena, A.M.; Aben, K.K.; Massuger, L.F.; Brooks-Wilson, A.; Kelemen, L.E.; Le, N.D.; Jakubowska, A.; Lubinski, J.; Medrek, K.; Stafford, A.; Easton, D.F.; Tyrer, J.; Bolton, K.L.; Harrington, P.; Eccles, D.; Chen, A.; Molina, A.N.; Davila, B.N.; Arango, H.; Tsai, Y.Y.; Chen, Z.; Risch, H.A.; McLaughlin, J.; Narod, S.A.; Ziogas, A.; Brewster, W.; Gentry-Maharaj, A.; Menon, U.; Wu, A.H.; Stram, D.O.; Pike, M.C.; Beesley, J.; Webb, P.M.; Chen, X.; Ekici, A.B.; Thiel, F.C.; Beckmann, M.W.; Yang, H.; Wentzensen, N.; Lissowska, J.; Fasching, P.A.; Despierre, E.; Amant, F.; Vergote, I.; Doherty, J.; Hein, R.; Wang-Gohrke, S.; Lurie, G.; Carney, M.E.; Thompson, P.J.; Runnebaum, I.; Hillemanns, P.; Dürst, M.; Antonenkova, N.; Bogdanova, N.; Leminen, A.; Butzow, R.; Heikkinen, T.; Stefansson, K.; Sulem, P.; Besenbacher, S.; Sellers, T.A.; Gayther, S.A.; Pharoah, P.D. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet., 2010, 42(10), 874-879.[http://dx.doi.org/10.1038/ng.668] [PMID: 20852632]
[17]
Corsi, J.M.; Rouer, E.; Girault, J.A.; Enslen, H. Organization and post-transcriptional processing of focal adhesion kinase gene. BMC Genomics, 2006, 7, 198.[http://dx.doi.org/10.1186/1471-2164-7-198] [PMID: 16889663]
[18]
Cance, W.G.; Golubovskaya, V.M. Focal adhesion kinase versus p53: apoptosis or survival? Sci. Signal., 2008, 1(20), pe22.[http://dx.doi.org/10.1126/stke.120pe22] [PMID: 18493017]
[19]
Walker, S.; Foster, F.; Wood, A.; Owens, T.; Brennan, K.; Streuli, C.H.; Gilmore, A.P. Oncogenic activation of FAK drives apoptosis suppression in a 3D-culture model of breast cancer initiation. Oncotarget, 2016, 7(43), 70336-70352.[http://dx.doi.org/10.18632/oncotarget.11856] [PMID: 27611942]
[20]
Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature, 2011, 474, 609-615.[http://dx.doi.org/10.1038/nature10166]
[21]
Comprehensive molecular portraits of human breast tumours. Nature, 2012, 490(7418), 61-70.[http://dx.doi.org/10.1038/nature11412] [PMID: 23000897]
[22]
Ward, K.K.; Tancioni, I.; Lawson, C.; Miller, N.L.G.; Jean, C.; Chen, X.L.; Uryu, S.; Kim, J.; Tarin, D.; Stupack, D.G.; Plaxe, S.C.; Schlaepfer, D.D. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin. Exp. Metastasis, 2013, 30(5), 579-594.[http://dx.doi.org/10.1007/s10585-012-9562-5] [PMID: 23275034]
[23]
Li, S.; Huang, X.; Zhang, D.; Huang, Q.; Pei, G.; Wang, L.; Jiang, W.; Hu, Q.; Tan, R.; Hua, Z.C. Requirement of PEA3 for transcriptional activation of FAK gene in tumor metastasis. PLoS One, 2013, 8(11), e79336.[http://dx.doi.org/10.1371/journal.pone.0079336] [PMID: 24260201]
[24]
Lim, S.T. Nuclear FAK: a new mode of gene regulation from cellular adhesions. Mol. Cells, 2013, 36(1), 1-6.[http://dx.doi.org/10.1007/s10059-013-0139-1] [PMID: 23686429]
[25]
Zhou, J.; Yi, Q.; Tang, L. The roles of nuclear focal adhesion kinase (FAK) on Cancer: a focused review. J. Exp. Clin. Cancer Res., 2019, 38(1), 250.[http://dx.doi.org/10.1186/s13046-019-1265-1] [PMID: 31186061]
[26]
Lim, S.T.; Chen, X.L.; Tomar, A.; Miller, N.L.; Yoo, J.; Schlaepfer, D.D. Knock-in mutation reveals an essential role for focal adhesion kinase activity in blood vessel morphogenesis and cell motility-polarity but not cell proliferation. J. Biol. Chem., 2010, 285(28), 21526-21536.[http://dx.doi.org/10.1074/jbc.M110.129999] [PMID: 20442405]
[27]
Sun, S.; Wu, H.J.; Guan, J.L. Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice. Sci. Rep., 2018, 8(1), 2550.[http://dx.doi.org/10.1038/s41598-018-20930-z] [PMID: 29416084]
[28]
Canel, M.; Byron, A.; Sims, A.H.; Cartier, J.; Patel, H.; Frame, M.C.; Brunton, V.G.; Serrels, B.; Serrels, A. Nuclear Fak and Runx1 cooperate to regulate IGFBP3, cell-cycle progression, and tumor growth. Cancer Res., 2017, 77(19), 5301-5312.[http://dx.doi.org/10.1158/0008-5472.CAN-17-0418] [PMID: 28807942]
[29]
Serrels, A.; Lund, T.; Serrels, B.; Byron, A.; McPherson, R.C.; von Kriegsheim, A.; Gómez-Cuadrado, L.; Canel, M.; Muir, M.; Ring, J.E.; Maniati, E.; Sims, A.H.; Pachter, J.A.; Brunton, V.G.; Gilbert, N.; Anderton, S.M.; Nibbs, R.J.B.; Frame, M.C. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell, 2015, 163(1), 160-173.[http://dx.doi.org/10.1016/j.cell.2015.09.001] [PMID: 26406376]
[30]
Ceccarelli, D.F.J.; Song, H.K.; Poy, F.; Schaller, M.D.; Eck, M.J. Crystal structure of the FERM domain of focal adhesion kinase. J. Biol. Chem., 2006, 281(1), 252-259.[http://dx.doi.org/10.1074/jbc.M509188200] [PMID: 16221668]
[31]
Leu, T.H.; Maa, M.C. Tyr-863 phosphorylation enhances focal adhesion kinase autophosphorylation at Tyr-397. Oncogene, 2002, 21(46), 6992-7000.[http://dx.doi.org/10.1038/sj.onc.1205904] [PMID: 12370821]
[32]
van Nimwegen, M.J.; van de Water, B. Focal adhesion kinase: a potential target in cancer therapy. Biochem. Pharmacol., 2007, 73(5), 597-609.[http://dx.doi.org/10.1016/j.bcp.2006.08.011] [PMID: 16997283]
[33]
Mitra, S.K.; Schlaepfer, D.D. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr. Opin. Cell Biol., 2006, 18(5), 516-523.[http://dx.doi.org/10.1016/j.ceb.2006.08.011] [PMID: 16919435]
[34]
Jain, M.H.; Somani, R.R. Role of focal adhesion kinase inhibitors as anti-cancer agents. World J. Pharma. Res., 2016, 5(11), 1585-1602.[http://dx.doi.org/10.20959/wjpr201611-7367]
[35]
Schlaepfer, D.D.; Mitra, S.K.; Ilic, D. Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim. Biophys. Acta, 2004, 1692(2-3), 77-102.[http://dx.doi.org/10.1016/j.bbamcr.2004.04.008] [PMID: 15246681]
[36]
Canel, M.; Serrels, A.; Miller, D.; Timpson, P.; Serrels, B.; Frame, M.C.; Brunton, V.G. Quantitative in vivo imaging of the effects of inhibiting integrin signaling via Src and FAK on cancer cell movement: effects on E-cadherin dynamics. Cancer Res., 2010, 70(22), 9413-9422.[http://dx.doi.org/10.1158/0008-5472.CAN-10-1454] [PMID: 21045155]
[37]
Zhao, J.; Guan, J.L. Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev., 2009, 28(1-2), 35-49.[http://dx.doi.org/10.1007/s10555-008-9165-4] [PMID: 19169797]
[38]
Golubovskaya, V.M. Targeting focal adhesion kinase in cancer-part I. Anticancer. Agents Med. Chem., 2010, 10(10), 713.[http://dx.doi.org/10.2174/187152010794728693] [PMID: 21348852]
[39]
Kato, A.; Kato, K.; Miyazawa, H.; Kobayashi, H.; Noguchi, N.; Kawashiri, S. Focal adhesion kinase (Fak) overexpression and phosphorylation in oral squamous cell carcinoma and their clinicopathological significance. Pathol. Oncol. Res., 2020, 26(3), 1659-1667.[http://dx.doi.org/10.1007/s12253-019-00732-y] [PMID: 31522363]
[40]
Zhou, Y.; Shu, C.; Huang, Y. Fibronectin promotes cervical cancer tumorigenesis through activating FAK signaling pathway. J. Cell. Biochem., 2019, 120(7), 10988-10997.[http://dx.doi.org/10.1002/jcb.28282] [PMID: 30977220]
[41]
Fujii, T.; Koshikawa, K.; Nomoto, S.; Okochi, O.; Kaneko, T.; Inoue, S.; Yatabe, Y.; Takeda, S.; Nakao, A. Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J. Hepatol., 2004, 41(1), 104-111.[http://dx.doi.org/10.1016/j.jhep.2004.03.029] [PMID: 15246215]
[42]
Chen, Y.; Li, Q.; Tu, K.; Wang, Y.; Wang, X.; Liu, D.; Chen, C.; Liu, D.; Yang, R.; Qiu, W.; Kang, N. Focal adhesion kinase promotes hepatic stellate cell activation by regulating plasma membrane localization of TGFβ receptor 2. Hepatol Commun, 2019, 4(2), 268-283.[http://dx.doi.org/10.1002/hep4.1452] [PMID: 32025610]
[43]
Zhang, J.; Hochwald, S.N. The role of FAK in tumor metabolism and therapy. Pharmacol. Ther., 2014, 142(2), 154-163.[http://dx.doi.org/10.1016/j.pharmthera.2013.12.003] [PMID: 24333503]
[44]
Golubovskaya, V.M.; Finch, R.; Kweh, F.; Massoll, N.A.; Campbell-Thompson, M.; Wallace, M.R.; Cance, W.G. p53 regulates FAK expression in human tumor cells. Mol. Carcinog., 2008, 47(5), 373-382.[http://dx.doi.org/10.1002/mc.20395] [PMID: 17999388]
[45]
Tavora, B.; Batista, S.; Reynolds, L.E.; Jadeja, S.; Robinson, S.; Kostourou, V.; Hart, I.; Fruttiger, M.; Parsons, M.; Hodivala-Dilke, K.M. Endothelial FAK is required for tumour angiogenesis. EMBO Mol. Med., 2010, 2(12), 516-528.[http://dx.doi.org/10.1002/emmm.201000106] [PMID: 21154724]
[46]
Lechertier, T.; Hodivala-Dilke, K. Focal adhesion kinase and tumour angiogenesis. J. Pathol., 2012, 226(2), 404-412.[http://dx.doi.org/10.1002/path.3018] [PMID: 21984450]
[47]
Chen, Q.; Yi, B.; Ma, J.; Ning, J.; Wu, L.; Ma, D.; Lu, K.; Gu, J. α2-adrenoreceptor modulated FAK pathway induced by dexmedetomidine attenuates pulmonary microvascular hyper-permeability following kidney injury. Oncotarget, 2016, 7(35), 55990-56001.[http://dx.doi.org/10.18632/oncotarget.10809] [PMID: 27463003]
[48]
Jean, C.; Chen, X.L.; Nam, J.O.; Tancioni, I.; Uryu, S.; Lawson, C.; Ward, K.K.; Walsh, C.T.; Miller, N.L.; Ghassemian, M.; Turowski, P.; Dejana, E.; Weis, S.; Cheresh, D.A.; Schlaepfer, D.D. Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function. J. Cell Biol., 2014, 204(2), 247-263.[http://dx.doi.org/10.1083/jcb.201307067] [PMID: 24446483]
[49]
Xu, D.; Liu, T.; Lin, L.; Li, S.; Hang, X.; Sun, Y. Exposure to endosulfan increases endothelial permeability by transcellular and paracellular pathways in relation to cardiovascular diseases. Environ. Pollut., 2017, 223, 111-119.[http://dx.doi.org/10.1016/j.envpol.2016.12.051] [PMID: 28108160]
[50]
Hwang, J.S.; Eun, S.Y.; Ham, S.A.; Yoo, T.; Lee, W.J.; Paek, K.S.; Do, J.T.; Lim, D.S.; Seo, H.G. PPARδ modulates oxLDL-induced apoptosis of vascular smooth muscle cells through a TGF-β/FAK signaling axis. Int. J. Biochem. Cell Biol., 2015, 62, 54-61.[http://dx.doi.org/10.1016/j.biocel.2015.02.014] [PMID: 25732738]
[51]
Zheng, Y.; Lu, Z. Paradoxical roles of FAK in tumor cell migration and metastasis. Cell Cycle, 2009, 8(21), 3474-3479.[http://dx.doi.org/10.4161/cc.8.21.9846] [PMID: 19829089]
[52]
Bergmann, S.; Elbahesh, H. Targeting the proviral host kinase, FAK, limits influenza a virus pathogenesis and NFkB-regulated pro-inflammatory responses. Virology, 2019, 534, 54-63.[http://dx.doi.org/10.1016/j.virol.2019.05.020] [PMID: 31176924]
[53]
Mohanty, P.; Bhatnagar, S. In silico screening to identify inhibitors of growth factor receptor 2-focal adhesion kinase interaction for therapeutic treatment of pathological cardiac hypertrophy. Assay Drug Dev. Technol., 2019, 17(2), 58-67.[http://dx.doi.org/10.1089/adt.2018.887] [PMID: 30869527]
[54]
Taneja, N.; Neininger, A.C.; Bersi, M.R.; David, M.W.; Burnette, D.T. Focal adhesion kinase regulates early steps of myofibrillogenesis in cardiomyocytes. Cell Biol. (Henderson NV), 2018, 1-25.[http://dx.doi.org/10.1101/261248]
[55]
Franchi, M.V.; Ruoss, S.; Valdivieso, P.; Mitchell, K.W.; Smith, K.; Atherton, P.J.; Narici, M.V.; Flück, M. Regional regulation of focal adhesion kinase after concentric and eccentric loading is related to remodelling of human skeletal muscle. Acta Physiol. (Oxf.), 2018, 223(3), e13056.[http://dx.doi.org/10.1111/apha.13056] [PMID: 29438584]
[56]
Mohanty, A.; Pharaon, R.R.; Nam, A.; Salgia, S.; Kulkarni, P.; Massarelli, E. FAK-targeted and combination therapies for the treatment of cancer: an overview of phase I and II clinical trials. Expert Opin. Investig. Drugs, 2020, 29(4), 399-409.[http://dx.doi.org/10.1080/13543784.2020.1740680] [PMID: 32178538]
[57]
Cromm, P.M.; Samarasinghe, K.T.G.; Hines, J.; Crews, C.M. Addressing kinase-independent functions of Fak via PROTAC mediated degradation. J. Am. Chem. Soc., 2018, 140(49), 17019-17026.[http://dx.doi.org/10.1021/jacs.8b08008] [PMID: 30444612]
[58]
Gao, H.; Wu, Y.; Sun, Y.; Yang, Y.; Zhou, G.; Rao, Y. Design, synthesis, and evaluation of highly potent Fak-targeting PROTACs. ACS Med. Chem. Lett., 2019, 11(10), 1855-1862.[http://dx.doi.org/10.1021/acsmedchemlett.9b00372] [PMID: 33062164]
[59]
Avraham, H.; Park, S.Y.; Schinkmann, K.; Avraham, S. RAFTK/Pyk2-mediated cellular signalling. Cell. Signal., 2000, 12(3), 123-133.[http://dx.doi.org/10.1016/S0898-6568(99)00076-5] [PMID: 10704819]
[60]
Lev, S.; Moreno, H.; Martinez, R.; Canoll, P.; Peles, E.; Musacchio, J.M.; Plowman, G.D.; Rudy, B.; Schlessinger, J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature, 1995, 376(6543), 737-745.[http://dx.doi.org/10.1038/376737a0] [PMID: 7544443]
[61]
Duong, L.T.; Rodan, G.A. PYK2 is an adhesion kinase in macrophages, localized in podosomes and activated by beta(2)-integrin ligation. Cell Motil. Cytoskeleton, 2000, 47(3), 174-188.[http://dx.doi.org/10.1002/1097-0169(200011)47:3<174::AID-CM2>3.0.CO;2-N] [PMID: 11056520]
[62]
Klingbeil, C.K.; Hauck, C.R.; Hsia, D.A.; Jones, K.C.; Reider, S.R.; Schlaepfer, D.D. Targeting Pyk2 to β 1-integrin-containing focal contacts rescues fibronectin-stimulated signaling and haptotactic motility defects of focal adhesion kinase-null cells. J. Cell Biol., 2001, 152(1), 97-110.[http://dx.doi.org/10.1083/jcb.152.1.97] [PMID: 11149924]
[63]
Shen, T.; Guo, Q. Role of Pyk2 in human cancers. Med. Sci. Monit., 2018, 24, 8172-8182.[http://dx.doi.org/10.12659/MSM.913479] [PMID: 30425234]
[64]
Xing, L.; Rai, B.; Lunney, E.A. Scaffold mining of kinase hinge binders in crystal structure database. J. Comput. Aided Mol. Des., 2014, 28(1), 13-23.[http://dx.doi.org/10.1007/s10822-013-9700-4] [PMID: 24375079]
[65]
Song, Z.; Yang, Y.; Liu, Z.; Peng, X.; Guo, J.; Yang, X.; Wu, K.; Ai, J.; Ding, J.; Geng, M.; Zhang, A. Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases. J. Med. Chem., 2015, 58(1), 197-211.[http://dx.doi.org/10.1021/jm5005144] [PMID: 24785465]
[66]
Kath, J.C.; Luzzio, M.J. Pyrimidine derivatives for the treatment of abnormal cell growth their preparation and pharmaceutical compositions. Pfizer Inc. USA. WO2005111016, 2005.
[67]
Kath, J.C.; Luzzio, M.J. Preparation of diamino pyrimidines for the treatment of abnormal cell growth. Pfizer Inc. USA. US 20050256144, 2005.
[68]
Kath, J.C.; Luzzio, M.J. Preparation of pyrimidine derivatives for the treatment of abnormal cell growth USA. Pfizer Inc., US 20050256145, 2005.
[69]
Holmes, I.P.; Bergman, Y.; Lunniss, G.E.; Nikac, M.; Chol, N.; Hemley, C.F.; Walker, S.R.; Foitzik, R.C.; Ganame, D.; Lessene, R. Preparation of N-phenylpyrimidin-2-amines as selective Fak inhibitors. Cancer Ther. CRC US 20130022594, 2013.
[70]
Holmes, I.P.; Bergman, Y.; Lunniss, G.E.; Nikac, M.; Choi, N.; Hemley, C.F.; Walker, S.R.; Foitzik, R.C.; Ganame, D.; Lessene, R. Selective Fak inhibitors. Cancer Ther. CRC US 20130324546, 2015.
[71]
Schlaepfer, D. Method of promoting apoptosis and inhibiting cancer metastasis by administration focal adhesion kinase (FAK) inhibitor. Poniard Pharmac., Inc. USA. WO 2011019943, 2011.
[72]
Cance, W.G.; Pandey, R.K.; Kurenova, E.V.; Ethirajan, M. Kinase protein binding inhibitors. Health Research, Inc. USA. US 20150051245, 2015.
[73]
Cance, W.G.; Pandey, R.K.; Kurenova, E.V.; Ethirajan, M. Preparation of dimethylpyridinylalkyldiamine derivatives and analogs for use as kinase protein binding inhibitors. Roswell Park Cancer Institute, USA. WO 2013074517, 2013.
[74]
Lee, J.; Song, H.J.; Koh, J.S.; Lee, H.K.; Kim, Y.; Chang, S.; Kim, H.W.; Lim, S.H.; Choi, J.S.; Kim, J.H.; Kim, S.W. Preparation of kinase inhibitors for pharmaceutical applications. Genosco, Oscotec Inc., USA. WO 2011060295, 2011.
[75]
Lafrance, L.V.; Leber, J.D.; Li, M.; Verma, S.K. Preparation of benzimidazolecarboxamides as inhibitors of FAK for treatment of proliferative diseases. GlaxoSmithKline LLC, USA. WO 2010126922, 2010.
[76]
Chu, S.S.; Alegria, L.A.; Bender, S.L; Benedict, S. P.; Borchardt, A.J.; Kania, R.S.; Nambu, M.D.; Tempczyk-Russell, A.M.; Sarshar, S. Preparation of diaminothiazoles for inhibiting protein kinases. Agouron Pharmaceuticals, Inc., USA. Patent: WO 2000075120, 2000.
[77]
Van Camp, J.; Patel, J.R.; Swann, S. Preparation of benzodiazepinones as Fak kinase inhibitors for treatment of cancers. Abbott Laboratories, USA. WO 2012045194, 2012.
[78]
Alaoui-Jamali, M.A.; Bijian, K.; Tao, J. Compounds targeting the cell invasion protein complex, their pharmaceutical compositions and methods of use thereof. The Royal Institution for the Advancement of Learning/Mcgill University Can. and Ocean University of China., WO 2013059927, 2013.
[79]
Yin, Y.; Su, Y. Dithiocarbamates compounds serving as fak inhibitors. Beijing Xibo Pharmaceutical Research Co. CN 111072571, 2018.
[80]
Feger, D.; Klotzbuecher, A.; Kubbutat, M.; Horst, G.; Lingnau, A.; Schaechtele, C.; Totzke, F. Use of indolocarbazole imides as selective protein kinase inhibitors for treatment of hematological and solid tumors. KTB Tumorforschungsgesellschaft m.b.H., Germany., WO 2009047216, 2009.
[81]
Breslin, H. J.; Dorsey, B.; Gregory, R. Macrocyclic compounds as ALK, Fak and Jak2 inhibitors and their preparation and use for the treatment of ALK-Fak- and Jak2-mediated diseases. Cephalon, Inc., USA. WO 2012125603, 2012.
[82]
Adams, J.L.; Faitg, T.H.; Johnson, N.W.; Peng, X. Anilinopyridines as inhibitors of Fak. SmithKline Beecham Corporation, USA. WO 2009105498, 2009.
[83]
Harling, J.D.; Tinworth, C. Compounds for treating disorders associated with aberrant kinase activity by degrading said kinase. GlaxoSmithKline, UK. WO 2018033556, 2018.
[84]
Ding, Y.; Fei, Y.; Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci., 2020, 41(7), 464-474.[http://dx.doi.org/10.1016/j.tips.2020.04.005] [PMID: 32416934]
[85]
Jones, S.F.; Siu, L.L.; Bendell, J.C.; Cleary, J.M.; Razak, A.R.; Infante, J.R.; Pandya, S.S.; Bedard, P.L.; Pierce, K.J.; Houk, B.; Roberts, W.G.; Shreeve, S.M.; Shapiro, G.I. A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors. Invest. New Drugs, 2015, 33(5), 1100-1107.[http://dx.doi.org/10.1007/s10637-015-0282-y] [PMID: 26334219]
[86]
Shimizu, T.; Fukuoka, K.; Takeda, M.; Iwasa, T.; Yoshida, T.; Horobin, J.; Keegan, M.; Vaickus, L.; Chavan, A.; Padval, M.; Nakagawa, K. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol., 2016, 77(5), 997-1003.[http://dx.doi.org/10.1007/s00280-016-3010-1] [PMID: 27025608]
[87]
Su, Y.; Li, R.; Ning, X.; Lin, Z.; Zhao, X.; Zhou, J.; Liu, J.; Jin, Y.; Yin, Y. Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities. Eur. J. Med. Chem., 2019, 177, 32-46.[http://dx.doi.org/10.1016/j.ejmech.2019.05.048] [PMID: 31129452]
[88]
Luzzio, M. J.; Autry, C. L.; Bhattacharya, S. K.; Freeman-Cook, K.D.; Hayward, M. M.; Hulford, C. A.; Nelson, K. L.; Xiao, J.; Zhao, X. Preparation of sulfonyl amide derivatives for the treatment of abnormal cell growth. Pfizer Products Inc., USA. WO 2008129380, 2008.
[89]
Du, W.; Li, Y. Deuterated Defactinib compound and application. Hinova Pharmaceuticals Inc., Rep. China. WO 2019214587, 2019.
[90]
Roberts, W.G.; Ung, E.; Whalen, P.; Cooper, B.; Hulford, C.; Autry, C.; Richter, D.; Emerson, E.; Lin, J.; Kath, J.; Coleman, K.; Yao, L.; Martinez-Alsina, L.; Lorenzen, M.; Berliner, M.; Luzzio, M.; Patel, N.; Schmitt, E.; LaGreca, S.; Jani, J.; Wessel, M.; Marr, E.; Griffor, M.; Vajdos, F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res., 2008, 68(6), 1935-1944.[http://dx.doi.org/10.1158/0008-5472.CAN-07-5155] [PMID: 18339875]
[91]
Zhao, X.; Sun, W.; Puszyk, W.M.; Wallet, S.; Hochwald, S.; Robertson, K.; Liu, C. Focal adhesion kinase inhibitor PF573228 and death receptor 5 agonist lexatumumab synergistically induce apoptosis in pancreatic carcinoma. Tumour Biol., 2017, 39(5), 1010428317699120.[http://dx.doi.org/10.1177/1010428317699120] [PMID: 28459212]
[92]
Lederer, P.A.; Zhou, T.; Chen, W.; Epshtein, Y.; Wang, H.; Mathew, B.; Jacobson, J.R. Attenuation of murine acute lung injury by PF-573,228, an inhibitor of focal adhesion kinase. Vascul. Pharmacol., 2018, 110, 16-23.[http://dx.doi.org/10.1016/j.vph.2018.06.017] [PMID: 29969688]
[93]
Howe, G.A.; Xiao, B.; Zhao, H.; Al-Zahrani, K.N.; Hasim, M.S.; Villeneuve, J.; Sekhon, H.S.; Goss, G.D.; Sabourin, L.A.; Dimitroulakos, J.; Addison, C.L. Focal adhesion kinase inhibitors in combination with erlotinib demonstrate enhanced anti-tumor activity in non-small cell lung cancer. PLoS One, 2016, 11(3), e0150567.[http://dx.doi.org/10.1371/journal.pone.0150567] [PMID: 26962872]
[94]
Ott, G.R.; Cheng, M.; Learn, K.S.; Wagner, J.; Gingrich, D.E.; Lisko, J.G.; Curry, M.; Mesaros, E.F.; Ghose, A.K.; Quail, M.R.; Wan, W.; Lu, L.; Dobrzanski, P.; Albom, M.S.; Angeles, T.S.; Wells-Knecht, K.; Huang, Z.; Aimone, L.D.; Bruckheimer, E.; Anderson, N.; Friedman, J.; Fernandez, S.V.; Ator, M.A.; Ruggeri, B.A.; Dorsey, B.D. Discovery of clinical candidate CEP-37440, a selective inhibitor of focal adhesion kinase (Fak) and anaplastic lymphoma kinase (ALK). J. Med. Chem., 2016, 59(16), 7478-7496.[http://dx.doi.org/10.1021/acs.jmedchem.6b00487] [PMID: 27527804]
[95]
Brown, N.F.; Williams, M.; Arkenau, H.T.; Fleming, R.A.; Tolson, J.; Yan, L.; Zhang, J.; Singh, R.; Auger, K.R.; Lenox, L.; Cox, D.; Lewis, Y.; Plisson, C.; Searle, G.; Saleem, A.; Blagden, S.; Mulholland, P. A study of the focal adhesion kinase inhibitor GSK2256098 in patients with recurrent glioblastoma with evaluation of tumor penetration of [11C]GSK2256098. Neuro-oncol., 2018, 20(12), 1634-1642.[http://dx.doi.org/10.1093/neuonc/noy078] [PMID: 29788497]
[96]
Auger, K.R.; Smitheman, K.N.; Korenchuk, S.; McHugh, C.; Kruger, R.; Van Aller, G.S.; Smallwood, A.; Gontarek, R.R.; Faitg, T.; Johnson, N. 387 the focal adhesion kinase inhibitor GSK2256098: a potent and selective inhibitor for the treatment of cancer. Eur. J. Cancer, 2012, 48, 118.[http://dx.doi.org/10.1016/S0959-8049(12)72185-8]
[97]
Mak, G.; Soria, J.C.; Blagden, S.P.; Plummer, R.; Fleming, R.A.; Nebot, N.; Zhang, J.; Mazumdar, J.; Rogan, D.; Gazzah, A.; Rizzuto, I.; Greystoke, A.; Yan, L.; Tolson, J.; Auger, K.R.; Arkenau, H.T. A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours. Br. J. Cancer, 2019, 120(10), 975-981.[http://dx.doi.org/10.1038/s41416-019-0452-3] [PMID: 30992546]
[98]
Tiede, S.; Meyer-Schaller, N.; Kalathur, R.K.R.; Ivanek, R.; Fagiani, E.; Schmassmann, P.; Stillhard, P.; Häfliger, S.; Kraut, N.; Schweifer, N.; Waizenegger, I.C.; Bill, R.; Christofori, G. The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer. Oncogenesis, 2018, 7(9), 73.[http://dx.doi.org/10.1038/s41389-018-0083-1] [PMID: 30237500]
[99]
Verheijen, R.B.; van der Biessen, D.A.J.; Hotte, S.J.; Siu, L.L.; Spreafico, A.; de Jonge, M.J.A.; Pronk, L.C.; De Vos, F.Y.F.L.; Schnell, D.; Hirte, H.W.; Steeghs, N.; Lolkema, M.P. Randomized, open-label, crossover studies evaluating the effect of food and liquid formulation on the pharmacokinetics of the novel focal adhesion kinase (Fak) inhibitor BI 853520. Target. Oncol., 2019, 14(1), 67-74.[http://dx.doi.org/10.1007/s11523-018-00618-0] [PMID: 30742245]
[100]
Hirt, U.A.; Waizenegger, I.C.; Schweifer, N.; Haslinger, C.; Gerlach, D.; Braunger, J.; Weyer-Czernilofsky, U.; Stadtmüller, H.; Sapountzis, I.; Bader, G.; Zoephel, A.; Bister, B.; Baum, A.; Quant, J.; Kraut, N.; Garin-Chesa, P.; Adolf, G.R. Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype. Oncogenesis, 2018, 7(2), 21.[http://dx.doi.org/10.1038/s41389-018-0032-z] [PMID: 29472531]
[101]
Ai, M.; Wang, C.; Tang, Z.; Liu, K.; Sun, X.; Ma, T.; Li, Y.; Ma, X.; Li, L.; Chen, L. Design and synthesis of diphenylpyrimidine derivatives (DPPYs) as potential dual EGFR T790M and FAK inhibitors against a diverse range of cancer cell lines. Bioorg. Chem., 2020, 94, 103408.[http://dx.doi.org/10.1016/j.bioorg.2019.103408] [PMID: 31706682]
[102]
Liu, T.J.; LaFortune, T.; Honda, T.; Ohmori, O.; Hatakeyama, S.; Meyer, T.; Jackson, D.; de Groot, J.; Yung, W.K. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo . Mol. Cancer Ther., 2007, 6(4), 1357-1367.[http://dx.doi.org/10.1158/1535-7163.MCT-06-0476] [PMID: 17431114]
[103]
Kurio, N.; Shimo, T.; Fukazawa, T.; Takaoka, M.; Okui, T.; Hassan, N.M.; Honami, T.; Hatakeyama, S.; Ikeda, M.; Naomoto, Y.; Sasaki, A. Anti-tumor effect in human breast cancer by TAE226, a dual inhibitor for FAK and IGF-IR in vitro and in vivo . Exp. Cell Res., 2011, 317(8), 1134-1146.[http://dx.doi.org/10.1016/j.yexcr.2011.02.008] [PMID: 21338601]
[104]
Lietha, D.; Eck, M.J. Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation. PLoS One, 2008, 3(11), e3800.[http://dx.doi.org/10.1371/journal.pone.0003800] [PMID: 19030106]
[105]
Wu, F.; Xu, T.; He, G.; Ouyang, L.; Han, B.; Peng, C.; Song, X.; Xiang, M. Discovery of novel focal adhesion kinase inhibitors using a hybrid protocol of virtual screening approach based on multicomplex-based pharmacophore and molecular docking. Int. J. Mol. Sci., 2012, 13(12), 15668-15678.[http://dx.doi.org/10.3390/ijms131215668] [PMID: 23443087]
[106]
Moritake, H.; Saito, Y.; Sawa, D.; Sameshima, N.; Yamada, A.; Kinoshita, M.; Kamimura, S.; Konomoto, T.; Nunoi, H. TAE226, a dual inhibitor of focal adhesion kinase and insulin-like growth factor-I receptor, is effective for Ewing sarcoma. Cancer Med., 2019, 8(18), 7809-7821.[http://dx.doi.org/10.1002/cam4.2647] [PMID: 31692287]
[107]
Liu, H.; Wu, B.; Ge, Y.; Huang, J.; Song, S.; Wang, C.; Yao, J.; Liu, K.; Li, Y.; Li, Y.; Ma, X. Phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with enhanced activity against pancreatic cancer cell lines. Bioorg. Med. Chem., 2017, 25(24), 6313-6321.[http://dx.doi.org/10.1016/j.bmc.2017.09.041] [PMID: 29102081]
[108]
Wang, L.; Ai, M.; Yu, J.; Jin, L.; Wang, C.; Liu, Z.; Shu, X.; Tang, Z.; Liu, K.; Luo, H.; Guan, W.; Sun, X.; Ma, X. Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells. Eur. J. Med. Chem., 2019, 172, 154-162.[http://dx.doi.org/10.1016/j.ejmech.2019.04.004] [PMID: 30978560]
[109]
Dao, P.; Jarray, R.; Le Coq, J.; Lietha, D.; Loukaci, A.; Lepelletier, Y.; Hadj-Slimane, R.; Garbay, C.; Raynaud, F.; Chen, H. Synthesis of novel diarylamino-1,3,5-triazine derivatives as FAK inhibitors with anti-angiogenic activity. Bioorg. Med. Chem. Lett., 2013, 23(16), 4552-4556.[http://dx.doi.org/10.1016/j.bmcl.2013.06.038] [PMID: 23845217]
[110]
Dao, P.; Jarray, R.; Smith, N.; Lepelletier, Y.; Le Coq, J.; Lietha, D.; Hadj-Slimane, R.; Herbeuval, J-P.; Garbay, C.; Raynaud, F.; Chen, H. Inhibition of both focal adhesion kinase and fibroblast growth factor receptor 2 pathways induces anti-tumor and anti-angiogenic activities. Cancer Lett., 2014, 348(1-2), 88-99.[http://dx.doi.org/10.1016/j.canlet.2014.03.007] [PMID: 24657306]
[111]
Dao, P.; Lietha, D.; Etheve-Quelquejeu, M.; Garbay, C.; Chen, H. Synthesis of novel 1,2,4-triazine scaffold as FAK inhibitors with antitumor activity. Bioorg. Med. Chem. Lett., 2017, 27(8), 1727-1730.[http://dx.doi.org/10.1016/j.bmcl.2017.02.072] [PMID: 28284808]
[112]
Dao, P.; Smith, N.; Tomkiewicz-Raulet, C.; Yen-Pon, E.; Camacho-Artacho, M.; Lietha, D.; Herbeuval, J.P.; Coumoul, X.; Garbay, C.; Chen, H. Design, synthesis, and evaluation of novel imidazo[1,2-a][1,3,5]triazines and their derivatives as focal adhesion kinase inhibitors with antitumor activity. J. Med. Chem., 2015, 58(1), 237-251.[http://dx.doi.org/10.1021/jm500784e] [PMID: 25180654]
[113]
Choi, H.S.; Wang, Z.; Richmond, W.; He, X.; Yang, K.; Jiang, T.; Sim, T.; Karanewsky, D.; Gu, X-J.; Zhou, V.; Liu, Y.; Ohmori, O.; Caldwell, J.; Gray, N.; He, Y. Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 1. Bioorg. Med. Chem. Lett., 2006, 16(8), 2173-2176.[http://dx.doi.org/10.1016/j.bmcl.2006.01.053] [PMID: 16458503]
[114]
Wang, R.; Chen, Y.; Zhao, X.; Yu, S.; Yang, B.; Wu, T.; Guo, J.; Hao, C.; Zhao, D.; Cheng, M. Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents. Eur. J. Med. Chem., 2019, 183, 111716.[http://dx.doi.org/10.1016/j.ejmech.2019.111716] [PMID: 31550660]
[115]
Wang, R.; Zhao, X.; Yu, S.; Chen, Y.; Cui, H.; Wu, T.; Hao, C.; Zhao, D.; Cheng, M. Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study. Bioorg. Chem., 2020, 102, 104092.[http://dx.doi.org/10.1016/j.bioorg.2020.104092] [PMID: 32707280]
[116]
Wang, R.; Yu, S.; Zhao, X.; Chen, Y.; Yang, B.; Wu, T.; Hao, C.; Zhao, D.; Cheng, M. Design, synthesis, biological evaluation and molecular docking study of novel thieno[3,2-d]pyrimidine derivatives as potent FAK inhibitors. Eur. J. Med. Chem., 2020, 188, 112024.[http://dx.doi.org/10.1016/j.ejmech.2019.112024] [PMID: 31923858]
[117]
Gütschow, M.; Eynde, J.J.V.; Jampilek, J.; Kang, C.; Mangoni, A.A.; Fossa, P.; Karaman, R.; Trabocchi, A.; Scott, P.J.H.; Reynisson, J.; Rapposelli, S.; Galdiero, S.; Winum, J.Y.; Brullo, C.; Prokai-Tatrai, K.; Sharma, A.K.; Schapira, M.; Azuma, Y.T.; Cerchia, L.; Spetea, M.; Torri, G.; Collina, S.; Geronikaki, A.; García-Sosa, A.T.; Vasconcelos, M.H.; Sousa, M.E.; Kosalec, I.; Tuccinardi, T.; Duarte, I.F.; Salvador, J.A.R.; Bertinaria, M.; Pellecchia, M.; Amato, J.; Rastelli, G.; Gomes, P.A.C.; Guedes, R.C.; Sabatier, J.M.; Estévez-Braun, A.; Pagano, B.; Mangani, S.; Ragno, R.; Kokotos, G.; Brindisi, M.; González, F.V.; Borges, F.; Miloso, M.; Rautio, J.; Muñoz-Torrero, D. Breakthroughs in medicinal chemistry: new targets and mechanisms, new drugs, new hopes-7. Molecules, 2020, 25(13), 2968.[http://dx.doi.org/10.3390/molecules25132968] [PMID: 32605268]
[118]
de Pins, B.; Montalban, E.; Vanhoutte, P.; Giralt, A.; Girault, J.A. The non-receptor tyrosine kinase Pyk2 modulates acute locomotor effects of cocaine in D1 receptor-expressing neurons of the nucleus accumbens. Sci. Rep., 2020, 10(1), 6619.[http://dx.doi.org/10.1038/s41598-020-63426-5] [PMID: 32313025]
[119]
Azizi, R.; Fallahian, F.; Aghaei, M.; Salemi, Z. Down-regulation of DDR1 induces apoptosis and inhibits EMT through phosphorylation of Pyk2/MKK7 in DU-145 and Lncap-FGC prostate cancer cell lines. Anticancer. Agents Med. Chem., 2020, 20(8), 1009-1016.[http://dx.doi.org/10.2174/1871520620666200410075558] [PMID: 32275493]
[120]
Chaudhary, P.K.; Han, J.S.; Jee, Y.; Lee, S.H.; Kim, S. Pyk2 downstream of G12/13 pathways regulates platelet shape change through RhoA/p160ROCK. Biochem. Biophys. Res. Commun., 2020, 526(3), 738-743.[http://dx.doi.org/10.1016/j.bbrc.2020.03.130] [PMID: 32265034]
[121]
Xiang, H.; Zhang, J.; Lin, C.; Zhang, L.; Liu, B.; Ouyang, L.; Ouyang, L. Targeting autophagy-related protein kinases for potential therapeutic purpose. Acta Pharm. Sin. B, 2020, 10(4), 569-581.[http://dx.doi.org/10.1016/j.apsb.2019.10.003] [PMID: 32322463]
[122]
Dawson, J.C.; Serrels, B.; Byron, A.; Muir, M.T.; Makda, A.; García-Muñoz, A.; von Kriegsheim, A.; Lietha, D.; Carragher, N.O.; Frame, M.C. A synergistic anticancer Fak and HDAC inhibitor combination discovered by a novel chemical-genetic high-content phenotypic screen. Mol. Cancer Ther., 2020, 19(2), 637-649.[http://dx.doi.org/10.1158/1535-7163.MCT-19-0330] [PMID: 31784455]
[123]
Hou, J.; Tan, Y.; Su, C.; Wang, T.; Gao, Z.; Song, D.; Zhao, J.; Liao, Y.; Liu, X.; Jiang, Y.; Feng, Q.; Wan, Z.; Yu, Y. Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways. Comput. Struct. Biotechnol. J., 2019, 18, 125-136.[http://dx.doi.org/10.1016/j.csbj.2019.12.010] [PMID: 31969973]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy