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Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

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

Review Article

Current Status in the Discovery of Covalent Janus Kinase 3 (JAK3) Inhibitors

Author(s): Jun Dai*, LiXi Yang and Glynn Addison

Volume 19, Issue 18, 2019

Page: [1531 - 1543] Pages: 13

DOI: 10.2174/1389557519666190617152011

Price: $65

Abstract

The search for inhibitors of the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) has been ongoing for several decades and has resulted in a number of JAK inhibitors being approved for use in patients, such as tofacitinib for the treatment of autoimmune diseases such as Rheumatoid Arthritis (RA). Although initially thought to be a JAK3 selective inhibitor, tofacitinib was subsequently found to possess significant activity to inhibit JAK1 and JAK2 which has contributed to some adverse side effects. A selective JAK3 inhibitor should only have an effect within the immune system since JAK3 is solely expressed in lymphoid tissue; this makes JAK3 a target of interest in the search for treatments of autoimmune diseases. A method to obtain selectivity for JAK3 over the other JAK family members, which has attracted more scientific attention recently, is the targeting of the active site cysteine residue, unique in JAK3 within the JAK family, with compounds containing electrophilic warheads which can form a covalent bond with the nucleophilic thiol of the cysteine residue. This review encompasses the historical search for a covalent JAK3 inhibitor and the most recently published research which hasn’t been reviewed to date. The most important compounds from the publications reviewed the activity and selectivity of these compounds together with some of the more important biological results are condensed in to an easily digested form that should prove useful for those interested in the field.

Keywords: Janus kinase, JAK3, covalent, selective, inhibitor, auto-immune disease.

Graphical Abstract
[1]
O’Shea, J.J.; Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity, 2012, 36(4), 542-550.
[http://dx.doi.org/10.1016/j.immuni.2012.03.014] [PMID: 22520847]
[2]
Villarino, A.V.; Kanno, Y.; Ferdinand, J.R.; O’Shea, J.J. Mechanisms of Jak/STAT signaling in immunity and disease. J. Immunol., 2015, 194(1), 21-27.
[http://dx.doi.org/10.4049/jimmunol.1401867] [PMID: 25527793]
[3]
O’Shea, J.J.; Holland, S.M.; Staudt, L.M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med., 2013, 368(2), 161-170.
[http://dx.doi.org/10.1056/NEJMra1202117] [PMID: 23301733]
[4]
O’Shea, J.J.; Schwartz, D.M.; Villarino, A.V.; Gadina, M.; McInnes, I.B.; Laurence, A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med., 2015, 66, 311-328.
[http://dx.doi.org/10.1146/annurev-med-051113-024537] [PMID: 25587654]
[5]
Shuai, K.; Liu, B. Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol., 2003, 3(11), 900-911.
[http://dx.doi.org/10.1038/nri1226] [PMID: 14668806]
[6]
Aringer, M.; Hofmann, S.R.; Frucht, D.M.; Chen, M.; Centola, M.; Morinobu, A.; Visconti, R.; Kastner, D.L.; Smolen, J.S.; O’Shea, J.J. Characterization and analysis of the proximal Janus kinase 3 promoter. J. Immunol., 2003, 170(12), 6057-6064.
[http://dx.doi.org/10.4049/jimmunol.170.12.6057] [PMID: 12794134]
[7]
O’Shea, J.J.; Pesu, M.; Borie, D.C.; Changelian, P.S. A new modality for immunosuppression: Targeting the JAK/STAT pathway. Nat. Rev. Drug Discov., 2004, 3(7), 555-564.
[http://dx.doi.org/10.1038/nrd1441] [PMID: 15232577]
[8]
Flanagan, M.E.; Blumenkopf, T.A.; Brissette, W.H.; Brown, M.F.; Casavant, J.M.; Shang-Poa, C.; Doty, J.L.; Elliott, E.A.; Fisher, M.B.; Hines, M.; Kent, C.; Kudlacz, E.M.; Lillie, B.M.; Magnuson, K.S.; McCurdy, S.P.; Munchhof, M.J.; Perry, B.D.; Sawyer, P.S.; Strelevitz, T.J.; Subramanyam, C.; Sun, J.; Whipple, D.A.; Changelian, P.S. Discovery of CP-690,550: A potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection. J. Med. Chem., 2010, 53(24), 8468-8484.
[http://dx.doi.org/10.1021/jm1004286] [PMID: 21105711]
[9]
Clark, J.D.; Flanagan, M.E.; Telliez, J.B. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J. Med. Chem., 2014, 57(12), 5023-5038.
[http://dx.doi.org/10.1021/jm401490p] [PMID: 24417533]
[10]
Meyer, D.M.; Jesson, M.I.; Li, X.; Elrick, M.M.; Funckes-Shippy, C.L.; Warner, J.D.; Gross, C.J.; Dowty, M.E.; Ramaiah, S.K.; Hirsch, J.L.; Saabye, M.J.; Barks, J.L.; Kishore, N.; Morris, D.L. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J. Inflamm. (Lond.), 2010, 7, 41-53.
[http://dx.doi.org/10.1186/1476-9255-7-41] [PMID: 20701804]
[11]
Changelian, P.S.; Flanagan, M.E.; Ball, D.J.; Kent, C.R.; Magnuson, K.S.; Martin, W.H.; Rizzuti, B.J.; Sawyer, P.S.; Perry, B.D.; Brissette, W.H.; McCurdy, S.P.; Kudlacz, E.M.; Conklyn, M.J.; Elliott, E.A.; Koslov, E.R.; Fisher, M.B.; Strelevitz, T.J.; Yoon, K.; Whipple, D.A.; Sun, J.; Munchhof, M.J.; Doty, J.L.; Casavant, J.M.; Blumenkopf, T.A.; Hines, M.; Brown, M.F.; Lillie, B.M.; Subramanyam, C.; Shang-Poa, C.; Milici, A.J.; Beckius, G.E.; Moyer, J.D.; Su, C.; Woodworth, T.G.; Gaweco, A.S.; Beals, C.R.; Littman, B.H.; Fisher, D.A.; Smith, J.F.; Zagouras, P.; Magna, H.A.; Saltarelli, M.J.; Johnson, K.S.; Nelms, L.F.; Des Etages, S.G.; Hayes, L.S.; Kawabata, T.T.; Finco-Kent, D.; Baker, D.L.; Larson, M.; Si, M.S.; Paniagua, R.; Higgins, J.; Holm, B.; Reitz, B.; Zhou, Y.J.; Morris, R.E.; O’Shea, J.J.; Borie, D.C. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science, 2003, 302(5646), 875-878.
[http://dx.doi.org/10.1126/science.1087061] [PMID: 14593182]
[12]
Scott, L.J. Tofacitinib: A review of its use in adult patients with rheumatoid arthritis. Drugs, 2013, 73(8), 857-874.
[http://dx.doi.org/10.1007/s40265-013-0065-8] [PMID: 23716132]
[13]
Simmons, D.L. Targeting kinases: A new approach to treating inflammatory rheumatic diseases. Curr. Opin. Pharmacol., 2013, 13(3), 426-434.
[http://dx.doi.org/10.1016/j.coph.2013.02.008] [PMID: 23523202]
[14]
Williams, N.K.; Bamert, R.S.; Patel, O.; Wang, C.; Walden, P.M.; Wilks, A.F.; Fantino, E.; Rossjohn, J.; Lucet, I.S. Dissecting specificity in the Janus kinases: The structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J. Mol. Biol., 2009, 387(1), 219-232.
[http://dx.doi.org/10.1016/j.jmb.2009.01.041] [PMID: 19361440]
[15]
Gehringer, M.; Forster, M.; Pfaffenrot, E.; Bauer, S.M.; Laufer, S.A. Novel hinge-binding motifs for Janus kinase 3 inhibitors: a comprehensive structure-activity relationship study on tofacitinib bioisosteres. ChemMedChem, 2014, 9(11), 2516-2527.
[http://dx.doi.org/10.1002/cmdc.201402252] [PMID: 25139757]
[16]
Verstovsek, S.; Kantarjian, H.; Mesa, R.A.; Pardanani, A.D.; Cortes-Franco, J.; Thomas, D.A.; Estrov, Z.; Fridman, J.S.; Bradley, E.C.; Erickson-Viitanen, S.; Vaddi, K.; Levy, R.; Tefferi, A. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med., 2010, 363(12), 1117-1127.
[http://dx.doi.org/10.1056/NEJMoa1002028] [PMID: 20843246]
[17]
Fridman, J.S.; Scherle, P.A.; Collins, R.; Burn, T.C.; Li, Y.; Li, J.; Covington, M.B.; Thomas, B.; Collier, P.; Favata, M.F.; Wen, X.; Shi, J.; McGee, R.; Haley, P.J.; Shepard, S.; Rodgers, J.D.; Yeleswaram, S.; Hollis, G.; Newton, R.C.; Metcalf, B.; Friedman, S.M.; Vaddi, K. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: Preclinical characterization of INCB028050. J. Immunol., 2010, 184(9), 5298-5307.
[http://dx.doi.org/10.4049/jimmunol.0902819] [PMID: 20363976]
[18]
Ghoreschi, K.; Laurence, A.; O’Shea, J.J. Janus kinases in immune cell signaling. Immunol. Rev., 2009, 228(1), 273-287.
[http://dx.doi.org/10.1111/j.1600-065X.2008.00754.x] [PMID: 19290934]
[19]
Laurence, A.; Pesu, M.; Silvennoinen, O.; O’Shea, J. JAK kinases in health and disease: an update. Open Rheumatol. J., 2012, 6, 232-244.
[http://dx.doi.org/10.2174/1874312901206010232] [PMID: 23028408]
[20]
Thoma, G.; Drückes, P.; Zerwes, H.G. Selective inhibitors of the Janus kinase Jak3--Are they effective? Bioorg. Med. Chem. Lett., 2014, 24(19), 4617-4621.
[http://dx.doi.org/10.1016/j.bmcl.2014.08.046] [PMID: 25217444]
[21]
Haan, C.; Rolvering, C.; Raulf, F.; Kapp, M.; Drückes, P.; Thoma, G.; Behrmann, I.; Zerwes, H.G. Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem. Biol., 2011, 18(3), 314-323.
[http://dx.doi.org/10.1016/j.chembiol.2011.01.012] [PMID: 21439476]
[22]
Wrobleski, S.T.; Pitts, W.J. Advances in the discovery of small molecule JAK3 inhibitors. Annu. Rep. Med. Chem., 2009, 44, 247-264.
[http://dx.doi.org/10.1016/S0065-7743(09)04412-1]
[23]
Alicea-Velázquez, N.L.; Boggon, T.J. The use of structural biology in Janus kinase targeted drug discovery. Curr. Drug Targets, 2011, 12(4), 546-555.
[http://dx.doi.org/10.2174/138945011794751528] [PMID: 21126226]
[24]
He, L.; Pei, H.; Lan, T.; Tang, M.; Zhang, C.; Chen, L. Design and synthesis of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Arch. Pharm. (Weinheim), 2017, 350(11)e1700194
[http://dx.doi.org/10.1002/ardp.201700194] [PMID: 28944566]
[25]
Chrencik, J.E.; Patny, A.; Leung, I.K.; Korniski, B.; Emmons, T.L.; Hall, T.; Weinberg, R.A.; Gormley, J.A.; Williams, J.M.; Day, J.E.; Hirsch, J.L.; Kiefer, J.R.; Leone, J.W.; Fischer, H.D.; Sommers, C.D.; Huang, H.C.; Jacobsen, E.J.; Tenbrink, R.E.; Tomasselli, A.G.; Benson, T.E. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol., 2010, 400(3), 413-433.
[http://dx.doi.org/10.1016/j.jmb.2010.05.020] [PMID: 20478313]
[26]
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]
[27]
Sanderson, K. Irreversible kinase inhibitors gain traction. Nat. Rev. Drug Discov., 2013, 12(9), 649-651.
[http://dx.doi.org/10.1038/nrd4103] [PMID: 23989776]
[28]
Yver, A. Osimertinib (AZD9291)-a science-driven, collaborative approach to rapid drug design and development. Ann. Oncol., 2016, 27(6), 1165-1170.
[http://dx.doi.org/10.1093/annonc/mdw129] [PMID: 26961148]
[29]
Baillie, T.A. Targeted covalent inhibitors for drug design. Angew. Chem. Int. Ed. Engl., 2016, 55(43), 13408-13421.
[http://dx.doi.org/10.1002/anie.201601091] [PMID: 27539547]
[30]
Vankayalapati, H.; Yer-Ramreddy, V.; Gangireddy, P.; Appalaneni, R.P. R.P. 3,5-(un)substituted-1H-pyrrolo[2,3-B]pyridine, 1H-pyrazolo [3,4-B]pyridine and 5H-pyrrolo[2,3-B]pyrazine dual ITK and JAK3 kinase inhibitors. WO2014172513(A1), October 23 . 2014.
[31]
Ramsden, N.; Dagostin, C. [4,3-C] pyridine derivatives as kinase inhibitors WO2013041605(A1), March 28 . 2013.
[32]
Styles, M.L.; Zeng, J.; Treutlein, H.R.; Wilks, A.F.; Kling, M.R.; Bu, X.; Burns, C.J. Selective kinase inhibitors. WO2005066156 (A1); July 21 . 2005.
[33]
Gray, N.; Tan, L. Janus kinase inhibitors and uses therof. WO2015164614(A1); October 29 . 2015.
[34]
Sim, J.Y.; Lee, K.I.; Kim, H.S.; Ha, T.H.; Suh, K.H. Triazolopyridine derivatives as a tyrosine kinase inhibitor. WO2013118986(A1), August 15 . 2013.
[35]
Ahearn, S.P.; Christopher, M.; Jung, J.; Pu, Q.; Rivkin, A.; Scott, M.E.; Witter, D.J.; Woo, H.C.; Cash, B.; Dinsmore, C.; Guerin, D. Pyrrolopyrimidines as Janus kinase inhibitors. WO2013085802 (A1), June 13 . 2013.
[36]
Brown, M.F.; Casimiro-garcia, A.; Che, Y.; Coe, J.W.; Flanagan, M.E.; Gilbert, A.M.; Hayward, M.M.; Langille, J.D.; Montgomery, J.I.; Telliez, J.B.; Thorarensen, A.; Unwalla, R.J. Pyrrolo[2,3-D] pyrimidinyl, pyrrolo[2,3-B]pyridinyl acrylamides. WO2015083028, June 11 . 2015.
[37]
Goldstein, D.M. Azaindole derivatives as JAK3 inhibitors. WO2014081732(A1), May 30 . 2014.
[38]
Brown, G.R.; Bamford, A.M.; Bowyer, J.; James, D.S.; Rankine, N.; Tang, E.; Torr, V.; Culbert, E.J. Naphthyl ketones: A new class of Janus kinase 3 inhibitors. Bioorg. Med. Chem. Lett., 2000, 10(6), 575-579.
[http://dx.doi.org/10.1016/S0960-894X(00)00051-2] [PMID: 10741557]
[39]
Dimmock, J.R.; Vashishtha, S.C.; Quail, J.W.; Pugazhenthi, U.; Zimpel, Z.; Sudom, A.M.; Allen, T.M.; Kao, G.Y.; Balzarini, J.; De Clercq, E. 4-(β-Arylvinyl)-3-(β-arylvinylketo)-1-ethyl-4-piperidinols and related compounds: A novel class of cytotoxic and anticancer agents. J. Med. Chem., 1998, 41(21), 4012-4020.
[http://dx.doi.org/10.1021/jm9801455] [PMID: 9767639]
[40]
Zambaldo, C.; Sadhu, K.K.; Karthikeyan, G.; Barluenga, S.; Daguer, J.P.; Winssinger, N. Selective affinity-based probe for oncogenic kinases suitable for live cell imaging. Chem. Sci. (Camb.), 2013, 4, 2088-2092.
[http://dx.doi.org/10.1039/c3sc21856b]
[41]
Schirmer, A.; Kennedy, J.; Murli, S.; Reid, R.; Santi, D.V. Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. Proc. Natl. Acad. Sci. USA, 2006, 103(11), 4234-4239.
[http://dx.doi.org/10.1073/pnas.0600445103] [PMID: 16537514]
[42]
London, N.; Miller, R.M.; Krishnan, S.; Uchida, K.; Irwin, J.J.; Eidam, O.; Gibold, L.; Cimermančič, P.; Bonnet, R.; Shoichet, B.K.; Taunton, J. Covalent docking of large libraries for the discovery of chemical probes. Nat. Chem. Biol., 2014, 10(12), 1066-1072.
[http://dx.doi.org/10.1038/nchembio.1666] [PMID: 25344815]
[43]
Tan, L.; Akahane, K.; McNally, R.; Reyskens, K.M.S.E.; Ficarro, S.B.; Liu, S.; Herter-Sprie, G.S.; Koyama, S.; Pattison, M.J.; Labella, K.; Johannessen, L.; Akbay, E.A.; Wong, K.K.; Frank, D.A.; Marto, J.A.; Look, T.A.; Arthur, J.S.C.; Eck, M.J.; Gray, N.S. Development of selective covalent Janus kinase 3 inhibitors. J. Med. Chem., 2015, 58(16), 6589-6606.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00710] [PMID: 26258521]
[44]
Goedken, E.R.; Argiriadi, M.A.; Banach, D.L.; Fiamengo, B.A.; Foley, S.E.; Frank, K.E.; George, J.S.; Harris, C.M.; Hobson, A.D.; Ihle, D.C.; Marcotte, D.; Merta, P.J.; Michalak, M.E.; Murdock, S.E.; Tomlinson, M.J.; Voss, J.W. Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol. J. Biol. Chem., 2015, 290(8), 4573-4589.
[http://dx.doi.org/10.1074/jbc.M114.595181] [PMID: 25552479]
[45]
Van Epps, S.; Fiamengo, B.; Edmunds, J.; Ericsson, A.; Frank, K.; Friedman, M.; George, D.; George, J.; Goedken, E.; Kotecki, B.; Martinez, G.; Merta, P.; Morytko, M.; Shekhar, S.; Skinner, B.; Stewart, K.; Voss, J.; Wallace, G.; Wang, L.; Wang, L.; Wishart, N. Design and synthesis of tricyclic cores for kinase inhibition. Bioorg. Med. Chem. Lett., 2013, 23(3), 693-698.
[http://dx.doi.org/10.1016/j.bmcl.2012.11.108] [PMID: 23265875]
[46]
Smith, G.A.; Uchida, K.; Weiss, A.; Taunton, J. Essential biphasic role for JAK3 catalytic activity in IL-2 receptor signaling. Nat. Chem. Biol., 2016, 12(5), 373-379.
[http://dx.doi.org/10.1038/nchembio.2056] [PMID: 27018889]
[47]
Elwood, F.; Witter, D.J.; Piesvaux, J.; Kraybill, B.; Bays, N.; Alpert, C.; Goldenblatt, P.; Qu, Y.; Ivanovska, I.; Lee, H.H.; Chiu, C.S.; Tang, H.; Scott, M.E.; Deshmukh, S.V.; Zielstorff, M.; Byford, A.; Chakravarthy, K.; Dorosh, L.; Rivkin, A.; Klappenbach, J.; Pan, B.S.; Kariv, I.; Dinsmore, C.; Slipetz, D.; Dandliker, P.J. Evaluation of JAK3 biology in autoimmune disease using a highly selective, irreversible JAK3 inhibitor. J. Pharmacol. Exp. Ther., 2017, 361(2), 229-244.
[http://dx.doi.org/10.1124/jpet.116.239723] [PMID: 28193636]
[48]
Stolina, M.; Bolon, B.; Middleton, S.; Dwyer, D.; Brown, H.; Duryea, D.; Zhu, L.; Rohner, A.; Pretorius, J.; Kostenuik, P.; Feige, U.; Zack, D. The evolving systemic and local biomarker milieu at different stages of disease progression in rat adjuvant-induced arthritis. J. Clin. Immunol., 2009, 29(2), 158-174.
[http://dx.doi.org/10.1007/s10875-008-9238-8] [PMID: 18726678]
[49]
Kempson, J.; Ovalle, D.; Guo, J.; Wrobleski, S.T.; Lin, S.; Spergel, S.H.; Duan, J.J.W.; Jiang, B.; Lu, Z.; Das, J.; Yang, B.V.; Hynes, J., Jr; Wu, H.; Tokarski, J.; Sack, J.S.; Khan, J.; Schieven, G.; Blatt, Y.; Chaudhry, C.; Salter-Cid, L.M.; Fura, A.; Barrish, J.C.; Carter, P.H.; Pitts, W.J. Discovery of highly potent, selective, covalent inhibitors of JAK3. Bioorg. Med. Chem. Lett., 2017, 27(20), 4622-4625.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.023] [PMID: 28927786]
[50]
Bhide, R.S.; Keon, A.; Weigelt, C.; Sack, J.S.; Schmidt, R.J.; Lin, S.; Xiao, H.Y.; Spergel, S.H.; Kempson, J.; Pitts, W.J.; Carman, J.; Poss, M.A. Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(21), 4908-4913.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.029] [PMID: 28947151]
[51]
Nakajima, Y.; Aoyama, N.; Takahashi, F.; Sasaki, H.; Hatanaka, K.; Moritomo, A.; Inami, M.; Ito, M.; Nakamura, K.; Nakamori, F.; Inoue, T.; Shirakami, S. Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3. Bioorg. Med. Chem., 2016, 24(19), 4711-4722.
[http://dx.doi.org/10.1016/j.bmc.2016.08.007] [PMID: 27544589]
[52]
He, L.; Shao, M.; Wang, T.; Lan, T.; Zhang, C.; Chen, L. Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors. Mol. Divers., 2018, 22(2), 343-358.
[http://dx.doi.org/10.1007/s11030-017-9803-2] [PMID: 29411195]
[53]
Pei, H.; He, L.; Shao, M.; Yang, Z.; Ran, Y.; Li, D.; Zhou, Y.; Tang, M.; Wang, T.; Gong, Y.; Chen, X.; Yang, S.; Xiang, M.; Chen, L. Discovery of a highly selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Sci. Rep., 2018, 8(1), 5273-5284.
[http://dx.doi.org/10.1038/s41598-018-23569-y] [PMID: 29588471]
[54]
Yin, Y.; Chen, C.J.; Yu, R.N.; Wang, Z.J.; Zhang, T.T.; Zhang, D.Y. Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors. Bioorg. Med. Chem., 2018, 26(17), 4774-4786.
[http://dx.doi.org/10.1016/j.bmc.2018.04.005] [PMID: 30139575]
[55]
Gehringer, M.; Forster, M.; Laufer, S.A. Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition. ACS Comb. Sci., 2015, 17(1), 5-10.
[http://dx.doi.org/10.1021/co500122h] [PMID: 25405713]
[56]
Knapp, S.; Arruda, P.; Blagg, J.; Burley, S.; Drewry, D.H.; Edwards, A.; Fabbro, D.; Gillespie, P.; Gray, N.S.; Kuster, B.; Lackey, K.E.; Mazzafera, P.; Tomkinson, N.C.O.; Willson, T.M.; Workman, P.; Zuercher, W.J. A public-private partnership to unlock the untargeted kinome. Nat. Chem. Biol., 2013, 9(1), 3-6.
[http://dx.doi.org/10.1038/nchembio.1113] [PMID: 23238671]
[57]
Quintás-Cardama, A.; Kantarjian, H.; Cortes, J.; Verstovsek, S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat. Rev. Drug Discov., 2011, 10(2), 127-140.
[http://dx.doi.org/10.1038/nrd3264] [PMID: 21283107]
[58]
Forster, M.; Chaikuad, A.; Bauer, S.M.; Holstein, J.; Robers, M.B.; Corona, C.R.; Gehringer, M.; Pfaffenrot, E.; Ghoreschi, K.; Knapp, S.; Laufer, S.A. Selective JAK3 inhibitors with a covalent reversible binding mode targeting a new induced fit binding pocket. Cell Chem. Biol., 2016, 23(11), 1335-1340.
[http://dx.doi.org/10.1016/j.chembiol.2016.10.008] [PMID: 27840070]
[59]
Serafimova, I.M.; Pufall, M.A.; Krishnan, S.; Duda, K.; Cohen, M.S.; Maglathlin, R.L.; McFarland, J.M.; Miller, R.M.; Frödin, M.; Taunton, J. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat. Chem. Biol., 2012, 8(5), 471-476.
[http://dx.doi.org/10.1038/nchembio.925] [PMID: 22466421]
[60]
Haan, C.; Rolvering, C.; Raulf, F.; Kapp, M.; Drückes, P.; Thoma, G.; Behrmann, I.; Zerwes, H.G. Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem. Biol., 2011, 18(3), 314-323.
[http://dx.doi.org/10.1016/j.chembiol.2011.01.012] [PMID: 21439476]
[61]
Thorarensen, A.; Banker, M.E.; Fensome, A.; Telliez, J.B.; Juba, B.; Vincent, F.; Czerwinski, R.M.; Casimiro-Garcia, A. ATP-mediated kinome selectivity: The missing link in understanding the contribution of individual JAK Kinase isoforms to cellular signaling. ACS Chem. Biol., 2014, 9(7), 1552-1558.
[http://dx.doi.org/10.1021/cb5002125] [PMID: 24814050]
[62]
Forster, M.; Chaikuad, A.; Dimitrov, T.; Döring, E.; Holstein, J.; Berger, B.T.; Gehringer, M.; Ghoreschi, K.; Müller, S.; Knapp, S.; Laufer, S.A. Development, optimization, and structure-activity relationships of covalent-reversible JAK3 inhibitors based on a tricyclic imidazo[5,4-d]pyrrolo[2,3-b]pyridine scaffold. J. Med. Chem., 2018, 61(12), 5350-5366.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00571] [PMID: 29852068]
[63]
Telliez, J.B.; Dowty, M.E.; Wang, L.; Jussif, J.; Lin, T.; Li, L.; Moy, E.; Balbo, P.; Li, W.; Zhao, Y.; Crouse, K.; Dickinson, C.; Symanowicz, P.; Hegen, M.; Banker, M.E.; Vincent, F.; Unwalla, R.; Liang, S.; Gilbert, A.M.; Brown, M.F.; Hayward, M.; Montgomery, J.; Yang, X.; Bauman, J.; Trujillo, J.I.; Casimiro-Garcia, A.; Vajdos, F.F.; Leung, L.; Geoghegan, K.F.; Quazi, A.; Xuan, D.; Jones, L.; Hett, E.; Wright, K.; Clark, J.D.; Thorarensen, A. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem. Biol., 2016, 11(12), 3442-3451.
[http://dx.doi.org/10.1021/acschembio.6b00677] [PMID: 27791347]
[64]
Thorarensen, A.; Dowty, M.E.; Banker, M.E.; Juba, B.; Jussif, J.; Lin, T.; Vincent, F.; Czerwinski, R.M.; Casimiro-Garcia, A.; Unwalla, R.; Trujillo, J.I.; Liang, S.; Balbo, P.; Che, Y.; Gilbert, A.M. Brown. M.F.; Hayward, M.; Montgomery, J.; Leung, L.; Yang, X.; Soucy, S.; Hegen, M.; Coe, J.; Langille, J.; Vajdos, F.; Chrencik, J.; Telliez. J.B. Design of a Janus kinase 3 (JAK3) specific inhibitor 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpi-peridin-1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signalling in humans. J. Med. Chem., 2017, 60, 1971-1993.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01694] [PMID: 28139931]
[65]
Leung, L.; Yang, X.; Strelevitz, T.J.; Montgomery, J.; Brown, M.F.; Zientek, M.A.; Banfield, C.; Gilbert, A.M.; Thorarensen, A.; Dowty, M.E. Clearance prediction of targeted covalent inhibitors by in vitro-in vivo extrapolation of hepatic and extrahepatic clearance mechanisms. Drug Metab. Dispos., 2017, 45(1), 1-7.
[http://dx.doi.org/10.1124/dmd.116.072983] [PMID: 27784718]
[66]
D’Amico, F.; Fiorino, G.; Furfaro, F.; Allocca, M.; Danese, S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin. Investig. Drugs, 2018, 27(7), 595-599.
[http://dx.doi.org/10.1080/13543784.2018.1492547] [PMID: 29938545]
[67]
Casimiro-Garcia, A.; Trujillo, J.I.; Vajdos, F.; Juba, B.; Banker, M.E.; Aulabaugh, A.; Balbo, P.; Bauman, J.; Chrencik, J.; Coe, J.W.; Czerwinski, R.; Dowty, M.; Knafels, J.D.; Kwon, S.; Leung, L.; Liang, S.; Robinson, R.P.; Telliez, J.B.; Unwalla, R.; Yang, X.; Thorarensen, A. Identification of cyanamide-based Janus kinase 3 (JAK3) covalent inhibitors. J. Med. Chem., 2018, 61(23), 10665-10699.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01308] [PMID: 30423248]
[68]
Falgueyret, J.P.; Oballa, R.M.; Okamoto, O.; Wesolowski, G.; Aubin, Y.; Rydzewski, R.M.; Prasit, P.; Riendeau, D.; Rodan, S.B.; Percival, M.D. Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J. Med. Chem., 2001, 44(1), 94-104.
[http://dx.doi.org/10.1021/jm0003440] [PMID: 11141092]
[69]
Rankin, A.L.; Seth, N.; Keegan, S.; Andreyeva, T.; Cook, T.A.; Edmonds, J.; Mathialagan, N.; Benson, M.J.; Syed, J.; Zhan, Y.; Benoit, S.E.; Miyashiro, J.S.; Wood, N.; Mohan, S.; Peeva, E.; Ramaiah, S.K.; Messing, D.; Homer, B.L.; Dunussi-Joannopoulos, K.; Nickerson-Nutter, C.L.; Schnute, M.E.; Douhan, J. III Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis. J. Immunol., 2013, 191(9), 4540-4550.
[http://dx.doi.org/10.4049/jimmunol.1301553] [PMID: 24068666]
[70]
Flanagan, M.E.; Abramite, J.A.; Anderson, D.P.; Aulabaugh, A.; Dahal, U.P.; Gilbert, A.M.; Li, C.; Montgomery, J.; Oppenheimer, S.R.; Ryder, T.; Schuff, B.P.; Uccello, D.P.; Walker, G.S.; Wu, Y.; Brown, M.F.; Chen, J.M.; Hayward, M.M.; Noe, M.C.; Obach, R.S.; Philippe, L.; Shanmugasundaram, V.; Shapiro, M.J.; Starr, J.; Stroh, J.; Che, Y. Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors. J. Med. Chem., 2014, 57(23), 10072-10079.
[http://dx.doi.org/10.1021/jm501412a] [PMID: 25375838]

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