Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases

Pharmacological Research

Volumn 111, Issue , 2016, Pages 784-803

  Roskoski, Robert ^a  

^a Blue Ridge Institute for Medical Research   (United States)

Author keywords

ATP binding site; Catalytic spine; K E D D; Regulatory spine; Ruxolitinib; Tofacitinib

Indexed keywords

ADENOSINE TRIPHOSPHATE; AMINO ACID; BARICITINIB; CYTOKINE; DECERNOTINIB; ERYTHROPOIETIN; FEDRATINIB; FILGOTINIB; GANDOTINIB; GROWTH HORMONE; HORMONE RECEPTOR; INTERFERON; INTERLEUKIN DERIVATIVE; JANUS KINASE 1; JANUS KINASE 2; JANUS KINASE 3; JANUS KINASE INHIBITOR; LESTAURTINIB; MOMELOTINIB; OCLACITINIB; PACRITINIB; PEFICITINIB; PHOSPHOTYROSINE; PROTEIN KINASE TYK2; RUXOLITINIB; STAT PROTEIN; THROMBOPOIETIN; TOFACITINIB; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; JANUS KINASE;

ATOPIC DERMATITIS; BINDING SITE; CELLULAR DISTRIBUTION; CROHN DISEASE; DOG DISEASE; DRUG MECHANISM; DRUG PROTEIN BINDING; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME LOCALIZATION; ENZYME REGULATION; GENE MUTATION; HEMATOPOIETIC CELL; HUMAN; INFLAMMATORY DISEASE; LEUKEMIA; LIGAND BINDING; LYMPHOMA; MYELOFIBROSIS; MYELOPROLIFERATIVE DISORDER; MYELOPROLIFERATIVE NEOPLASM; NEOPLASM; NON SMALL CELL LUNG CANCER; NONHUMAN; PANCREAS CANCER; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POLYCYTHEMIA VERA; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PRURITUS; PSORIASIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SKIN ALLERGY; SOLID TUMOR; THROMBOCYTHEMIA; ULCERATIVE COLITIS; ANIMAL; CHEMISTRY; CONSERVED SEQUENCE; DRUG EFFECTS; ENZYMOLOGY; INFLAMMATION; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PROTEIN CONFORMATION; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; AMINO ACIDS; ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; BINDING SITES; CONSERVED SEQUENCE; HUMANS; INFLAMMATION; JANUS KINASE INHIBITORS; JANUS KINASES; MOLECULAR TARGETED THERAPY; NEOPLASMS; PROTEIN CONFORMATION; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84979900297     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2016.07.038     Document Type: Review

References (91)

1. [1] Williams, N.K., Bamert, R.S., Patel, O., Wang, C., Walden, P.M., Wilks, A.F., et al. 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. 387 (2009), 219–232.
2. [2] Wilks, A.F., The JAK kinases: not just another kinase drug discovery target. Semin. Cell Dev. Biol. 19 (2008), 319–328.
3. [3] Kawamura, M., McVicar, D.W., Johnston, J.A., Blake, T.B., Chen, Y.Q., Lal, B.K., et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc. Natl. Acad. Sci. U. S. A. 91 (1994), 6374–6378.
4. [4] Manning, G., Whyte, D.B., Martinez, R., Hunter, T., Sudarsanam, S., The protein kinase complement of the human genome. Science 298 (2002), 1912–1934.
5. [5] 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. 66 (2015), 311–328.
6. [6] Haynes, B.F., Soderberg, K.A., Fauci, A.S., Introduction to the immune system. Longo, D.L., Kasper, D.L., Jameson, J.L., Fauci, A.S., Hauser, S.L., Loscalzo, J., (eds.) Harrison's Principles of Internal Medicine, 18th ed., 2012, McGraw Hill Medical, New York, 2650–2685.
7. [7] Babon, J.J., Lucet, I.S., Murphy, J.M., Nicola, N.A., Varghese, L.N., The molecular regulation of Janus kinase (JAK) activation. Biochem. J. 462 (2014), 1–13.
8. [8] Abroun, S., Saki, N., Ahmadvand, M., Asghari, F., Salari, F., Rahim, F., STATs: an old story yet mesmerizing. Cell J. 1:17 (2015), 395–411.
9. [9] Chen, X., Vinkemeier, U., Zhao, Y., Jeruzalmi, D., Darnell, J.E. Jr., Kuriyan, J., Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell 93 (1998), 827–839.
10. [10] Roskoski, R. Jr., A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol. Res. 100 (2015), 1–23.
11. [11] Irie-Sasaki, J., Sasaki, T., Matsumoto, W., Opavsky, A., Cheng, M., Welstead, G., et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 18:409 (2001), 349–354.
12. [12] Yamaoka, K., Saharinen, P., Pesu, M., Holt, V.E. 3rd, Silvennoinen, O., O'Shea, J.J., The janus kinases (Jaks). Genome Biol., 5, 2004, 253.
13. [13] Knighton, D.R., Zheng, J.H., Ten Eyck, L.F., Ashford, V.A., Xuong, N.H., Taylor, S.S., et al. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253 (1991), 407–414.
14. [14] Knighton, D.R., Zheng, J.H., Ten Eyck, L.F., Xuong, N.H., Taylor, S.S., Sowadski, J.M., Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253 (1991), 414–420.
15. [15] Taylor, S.S., Keshwani, M.M., Steichen, J.M., Kornev, A.P., Evolution of the eukaryotic protein kinases as dynamic molecular switches. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367 (2012), 2517–2528.
16. [16] Hanks, S.K., Hunter, T., Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9 (1995), 576–596.
17. [17] Meharena, H.S., Chang, P., Keshwani, M.M., Oruganty, K., Nene, A.K., Kannan, N., et al. Deciphering the structural basis of eukaryotic protein kinase regulation. PLoS Biol., 11, 2013, e1001680.
18. [18] Nolen, B., Taylor, S., Ghosh, G., Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell 15 (2004), 661–675.
19. [19] Chatti, K., Farrar, W.L., Duhé, R.J., Tyrosine phosphorylation of the Janus kinase 2 activation loop is essential for a high-activity catalytic state but dispensable for a basal catalytic state. Biochemistry 43 (2004), 4272–4283.
20. [20] Kornev, A.P., Haste, N.M., Taylor, S.S., Ten Eyck, L.F., Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 17783–17788.
21. [21] Kornev, A.P., Taylor, S.S., Ten Eyck, L.F., A helix scaffold for the assembly of active protein kinases. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 14377–14382.
22. [22] Roskoski, R. Jr., Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol. Res. 107 (2016), 249–275.
23. [23] Roskoski, R. Jr., Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol. Res. 94 (2015), 9–25.
24. [24] Roskoski, R. Jr., ErbB/HER protein-tyrosine kinases: structures and small molecule inhibitors. Pharmacol. Res. 87 (2014), 42–59.
25. [25] Roskoski, R. Jr., ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66 (2012), 105–143.
26. [26] Roskoski, R. Jr., MEK1/2 dual-specificity protein kinases: structure and regulation. Biochem. Biophys. Res. Commun. 417 (2012), 5–10.
27. [27] Roskoski, R. Jr., Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol. Res. 103 (2016), 26–48.
28. [28] Feng, J., Witthuhn, B.A., Matsuda, T., Kohlhuber, F., Kerr, I.M., Ihle, J.N., Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol. Cell. Biol. 17 (1997), 2497–2501.
29. [29] Zhou, Y.J., Hanson, E.P., Chen, Y.Q., Magnuson, K., Chen, M., Swann, P.G., et al. Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and negatively regulate its enzymatic activity. Proc. Natl. Acad. Sci. U. S. A. 94 (1997), 13850–13855.
30. [30] Gauzzi, M.C., Velazquez, L., McKendry, R., Mogensen, K.E., Fellous, M., Pellegrini, S., Interferon-α-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase. J. Biol. Chem. 271 (1996), 20494–20500.
31. [31] Saharinen, P., Takaluoma, K., Silvennoinen, O., Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol. Cell. Biol. 20 (2000), 3387–3395.
32. [32] Lupardus, P.J., Ultsch, M., Wallweber, H., Bir Kohli, P., Johnson, A.R., et al. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 8025–8030.
33. [33] Waters, M.J., Brooks, A.J., JAK2 activation by growth hormone and other cytokines. Biochem. J. 466 (2015), 1–11.
34. [34] Lu, X., Levine, R., Tong, W., Wernig, G., Pikman, Y., Zarnegar, S., et al. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation. Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 18962–18967.
35. [35] Waters, M.J., Brooks, A.J., Chhabra, Y., A new mechanism for growth hormone receptor activation of JAK2, and implications for related cytokine receptors. JAKSTAT, 3, 2014, e29569.
36. [36] Ishida-Takahashi, R., Rosario, F., Gong, Y., Kopp, K., Stancheva, Z., Chen, X., et al. Phosphorylation of Jak2 on Ser523 inhibits Jak2-dependent leptin receptor signaling. Mol. Cell. Biol. 26 (2006), 4063–4073 (Erratum in: Mol. Cell. Biol. 2006;26:6309).
37. [37] Mazurkiewicz-Munoz, A.M., Argetsinger, L.S., Kouadio, J.L., Stensballe, A., Jensen, O.N., Cline, J.M., et al. Phosphorylation of JAK2 at serine 523: a negative regulator of JAK2 that is stimulated by growth hormone and epidermal growth factor. Mol. Cell. Biol. 26 (2006), 4052–4062.
38. [38] Argetsinger, L.S., Kouadio, J.L., Steen, H., Stensballe, A., Jensen, O.N., Carter-Su, C., Autophosphorylation of JAK2 on tyrosines 221 and 570 regulates its activity. Mol. Cell. Biol. 24 (2004), 4955–4967.
39. [39] Argetsinger, L.S., Stuckey, J.A., Robertson, S.A., Koleva, R.I., Cline, J.M., Marto, J.A., et al. Tyrosines 868, 966, and 972 in the kinase domain of JAK2 are autophosphorylated and required for maximal JAK2 kinase activity. Mol. Endocrinol. 24 (2010), 1062–1076.
40. [40] Ungureanu, D., Wu, J., Pekkala, T., Niranjan, Y., Young, C., Jensen, O.N., et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol. 18 (2011), 971–976.
41. [41] Scott, D.L., Wolfe, F., Huizinga, T.W., Rheumatoid arthritis. Lancet 376 (2010), 1094–1108.
42. [42] van Vollenhoven, R.F., Fleischmann, R., Cohen, S., Lee, E.B., García Meijide, J.A., Wagner, S., et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 367 (2012), 508–519.
43. [43] Lee, E.B., Fleischmann, R., Hall, S., Wilkinson, B., Bradley, J.D., Gruben, D., et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370 (2014), 2377–2386.
44. [44] Dörner, T., Strand, V., Cornes, P., Gonçalves, J., Gulácsi, L., Kay, J., et al. The changing landscape of biosimilars in rheumatology. Ann. Rheum. Dis. 75 (2016), 974–982.
45. [45] Pucheu-Haston, C.M., Atopic dermatitis in the domestic dog. Clin. Dermatol. 34 (2016), 299–303.
46. [46] Santoro, D., Rodrigues Hoffmann, A., Canine and human atopic dermatitis: two faces of the same host-microbe interaction. J. Invest. Dermatol. 136 (2016), 1087–1089.
47. [47] Saridomichelakis, M.N., Olivry, T., An update on the treatment of canine atopic dermatitis. Vet. J. 207 (2016), 29–37.
48. [48] Schleicher, S.M., Psoriasis: pathogenesis, assessment, and therapeutic update. Clin. Podiatr. Med. Surg. 33 (2016), 355–366.
49. [49] Sofia, M.A., Rubin, D.T., Current approaches for optimizing the benefit of biologic therapy in ulcerative colitis. Ther. Adv. Gastroenterol. 9 (2016), 548–559.
50. [50] Baumgart, D.C., Sandborn, W.J., Crohn's disease. Lancet 380 (2012), 1590–1605.
51. [51] Bryan, J.C., Verstovsek, S., Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib. Cancer Chemother. Pharmacol., 2016, 10.1007/s00280-016-3012-z.
52. [52] Cervantes, F., Dupriez, B., Pereira, A., Passamonti, F., Reilly, J.T., Morra, E., et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 113 (2009), 2895–2901.
53. [53] Klampfl, T., Gisslinger, H., Harutyunyan, A.S., Nivarthi, H., Rumi, E., Milosevic, J.D., et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 369 (2013), 2379–2390.
54. [54] Geyer, H., Scherber, R., Kosiorek, H., Dueck, A.C., Kiladjian, J.J., Xiao, Z., et al. Symptomatic profiles of patients with polycythemia vera: implications of inadequately controlled disease. J. Clin. Oncol. 34 (2016), 151–159.
55. [55] Ma, X., Vanasse, G., Cartmel, B., Wang, Y., Selinger, H.A., Prevalence of polycythemia vera and essential thrombocythemia. Am. J. Hematol. 83 (2008), 359–362.
56. [56] Cerquozzi, S., Tefferi, A., Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J., 5, 2015, e366.
57. [57] Mesa, R.A., Silverstein, M.N., Jacobsen, S.J., Wollan, P.C., Tefferi, A., Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976–1995. Am. J. Hematol. 61 (1999), 10–15.
58. [58] Spivak, J.L., Considine, M., Williams, D.M., Talbot, C.C. Jr., Rogers, O., Moliterno, A.R., et al. Two clinical phenotypes in polycythemia vera. N. Engl. J. Med. 371 (2014), 808–817.
59. [59] Springuel, L., Renauld, J.C., Knoops, L., JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications. Haematologica 100 (2015), 1240–1253.
60. [60] Davis, M.I., Hunt, J.P., Herrgard, S., Ciceri, P., Wodicka, L.M., Pallares, G., et al. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 29 (2011), 1046–1051.
61. ®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J. Vet. Pharmacol. Ther. 37 (2014), 317–324.
62. [62] Farmer, L.J., Ledeboer, M.W., Hoock, T., Arnost, M.J., Bethiel, R.S., Bennani, Y.L., et al. Discovery of VX-509 (decernotinib): a potent and selective janus kinase 3 inhibitor for the treatment of autoimmune diseases. J. Med. Chem. 58 (2015), 7195–7216.
63. [63] Takeuchi, T., Tanaka, Y., Iwasaki, M., Ishikura, H., Saeki, S., Kaneko, Y., Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann. Rheum. Dis. 75 (2016), 1057–1064.
64. [64] Menet, C.J., Fletcher, S.R., Van Lommen, G., Geney, R., Blanc, J., Smits, K., et al. Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634. J. Med. Chem. 57 (2014), 9323–9342.
65. [65] Ma, L., Clayton, J.R., Walgren, R.A., Zhao, B., Evans, R.J., Smith, M.C., et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J., 3, 2013, e109.
66. [66] Poulsen, A., William, A., Blanchard, S., Lee, A., Nagaraj, H., Wang, H., et al. Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3). J. Comput. Aided Mol. Des. 26 (2012), 437–450.
67. [67] Chrencik, J.E., Patny, A., Leung, I.K., Korniski, B., Emmons, T.L., Hall, T., et al. Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J. Mol. Biol. 400 (2010), 413–433.
68. ®) in client-owned dogs with atopic dermatitis. Vet. Dermatol. 24 (2013), 587–597 e141–2.
69. [69] Little, P.R., King, V.L., Davis, K.R., Cosgrove, S.B., Stegemann, M.R., A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs. Vet. Dermatol. 26 (2015), 23–30.
70. [70] Friesner, R.A., Banks, J.L., Murphy, R.B., Halgren, T.A., Klicic, J.J., Mainz, D.T., et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47 (2004), 1739–1749.
71. [71] Keystone, E.C., Taylor, P.C., Drescher, E., Schlichting, D.E., Beattie, S.D., Berclaz, P.Y., et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann. Rheum. Dis. 74 (2015), 333–340.
72. [72] Genovese, M.C., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L., et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374 (2016), 1243–1252.
73. [73] Papp, K.A., Menter, M.A., Raman, M., Disch, D., Schlichting, D.E., Gaich, C., et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br. J. Dermatol. 174 (2016), 1266–1276.
74. [74] Verstovsek, S., Mesa, R.A., Gotlib, J., Levy, R.S., Gupta, V., DiPersio, J.F., et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 366 (2012), 799–807.
75. [75] Harrison, C., Kiladjian, J.J., Al-Ali, H.K., Gisslinger, H., Waltzman, R., Stalbovskaya, V., et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med. 366 (2012), 787–798.
76. [76] Verstovsek, S., Passamonti, F., Rambaldi, A., Barosi, G., Rosen, P.J., Rumi, E., et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 120 (2014), 513–520.
77. [77] Mahajan, S., Hogan, J.K., Shlyakhter, D., Oh, L., Salituro, F.G., Farmer, L., et al. VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. J. Pharmacol. Exp. Ther. 353 (2015), 405–414.
78. [78] Genovese, M.C., Yang, F., Østergaard, M., Kinnman, N., Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Ann. Rheum. Dis.(April 15), 2016 (pii: annrheumdis-2015-208901. 10.1136/annrheumdis-2015-208901 [Epub ahead of print]).
79. [79] Takeuchi, T., Tanaka, Y., Iwasaki, M., Ishikura, H., Saeki, S., Kaneko, Y., Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann. Rheum. Dis. 75 (2016), 1057–1064.
80. [80] Namour, F., Diderichsen, P.M., Cox, E., Vayssière, B., Van der Aa, A., Tasset, C., et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic modeling of filgotinib (glpg0634), a selective jak1 inhibitor, in support of phase iib dose selection. Clin. Pharmacokinet. 54 (2015), 859–874.
81. [81] Sherman, W., Day, T., Jacobson, M.P., Friesner, R.A., Farid, R., Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem. 49 (2006), 534–553.
82. [82] Pardanani, A., Gotlib, J.R., Jamieson, C., Cortes, J.E., Talpaz, M., Stone, R.M., et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J. Clin. Oncol. 29 (2011), 789–796.
83. [83] Tyner, J.W., Bumm, T.G., Deininger, J., Wood, L., Aichberger, K.J., Loriaux, M.M., et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood 115 (2010), 5232–5240.
84. [84] Pardanani, A., Laborde, R.R., Lasho, T.L., Finke, C., Begna, K., Al-Kali, A., et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 27 (2013), 1322–1327.
85. [85] Santos, F.P., Kantarjian, H.M., Jain, N., Manshouri, T., Thomas, D.A., Garcia-Manero, G., et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood 115 (2010), 1131–1136.
86. [86] Furqan, M., Mukhi, N., Lee, B., Liu, D., Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark. Res., 1, 2013, 5.
87. [87] Chow, V., Weissman, A., O'Connell, C.L., Mehrvar, A., Akhtari, M., Emerging treatment options for myelofibrosis: focus on pacritinib. OncoTargets Ther. 9 (2016), 2655–2665.
88. [88] Shah, K., Liu, Y., Deirmengian, C., Shokat, K.M., Engineering unnatural nucleotide specificity for Rous sarcoma virus tyrosine kinase to uniquely label its direct substrates. Proc. Natl. Acad. Sci. U. S. A. 94 (1997), 3565–3570.
89. [89] Liu, Y., Shah, K., Yang, F., Witucki, L., Shokat, K.M., A molecular gate which controls unnatural ATP analogue recognition by the tyrosine kinase v-Src. Bioorg. Med. Chem. 6 (1998), 1219–1226.
90. [90] Roth, B.L., Sheffler, D.J., Kroeze, W.K., Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat. Rev. Drug Discov. 3 (2004), 353–359.
91. [91] Cohen, P., Alessi, D.R., Kinase drug discovery—what's next in the field?. ACS Chem. Biol. 8 (2013), 96–104.