Selective JAK inhibitors

Future Medicinal Chemistry

Volumn 6, Issue 12, 2014, Pages 1439-1471

  Dymock, Brian W ^a   Yang, Eugene Guorong ^a   Chu Farseeva, Yuyi ^a   Yao, Lianbin ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

[No Author keywords available]

Indexed keywords

5 CHLORO N2 [1 (5 FLUORO 2 PYRIMIDINYL)ETHYL] N4 (5 METHYL 1H PYRAZOL 3 YL) 2,4 PYRIMIDINEDIAMINE; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; BARICITINIB; CAPECITABINE; DECERNOTINIB; FEDRATINIB; FILGOTINIB; GANDOTINIB; JANUS KINASE 1; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; JANUS KINASE 3; JANUS KINASE 3 INHIBITOR; JANUS KINASE INHIBITOR; LESTAURTINIB; MOMELOTINIB; N TERT BUTYL 3 [5 METHYL 2 [4 (4 METHYL 1 PIPERAZINYL)PHENYLAMINO] 4 PYRIMIDINYLAMINO]BENZENESULFONAMIDE; PACRITINIB; PROTEIN KINASE TYK2; RUXOLITINIB; SELECTIVE JANUS KINASE 1 INHIBITOR; SELECTIVE JANUS KINASE INHIBITOR; SELECTIVE PROTEIN KINASE TYK2 INHIBITOR; TOFACITINIB; UNCLASSIFIED DRUG; JANUS KINASE; PROTEIN KINASE INHIBITOR;

ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; CANCER INHIBITION; CELLULAR DISTRIBUTION; CRYSTAL STRUCTURE; DRUG BINDING SITE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG HALF LIFE; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG SELECTIVITY; HUMAN; HYDROGEN BOND; IC50; IMMUNOSUPPRESSIVE TREATMENT; NONHUMAN; REVIEW; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DOSE RESPONSE; ENZYME SPECIFICITY;

ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; JANUS KINASES; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PROTEIN KINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 84908144927     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/FMC.14.92     Document Type: Review

References (134)

1. Menet CJ, Rompaey LV, Geney R. Advances in the discovery of selective JAK inhibitors. Prog. Med. Chem. 52, 153-223 (2013).
2. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J. Med. Chem. 57(12), 5023-5038 (2014). • Very informative review bringing the reader up to date on the inflammatory disease applications of JAK inhibitors.
3. Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr. Med. Chem. 19(26), 4399-4413 (2012).
4. Baxter EJ, Scott LM, Campbell PJ et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365(9464), 1054-1061 (2005).
5. James C, Ugo V, Le Couedic JP et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434(7037), 1144-1148 (2005).
6. Kralovics R, Passamonti F, Buser AS et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352(17), 1779-1790 (2005).
7. Levine RL, Wadleigh M, Cools J et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7(4), 387-397 (2005).
8. Verstovsek S, Kantarjian H, Mesa RA et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363(12), 1117-1127 (2010).
9. Dowty ME, Jesson MI, Ghosh S et al. Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis. J. Pharmacol. Exp. Ther. 348(1), 165-173 (2014).
10. Cutolo M. The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: latest findings and clinical potential. Ther. Adv. Musculoskelet. Dis. 5(1), 3-11 (2013).
11. William W. Study of Ruxolitinib in Pancreatic Cancer Patients (RECAP). www.clinicaltrials.gov/show/NCT01423604
12. Ruxolitinib Plus Capecitabine Improves Survival in Pancreatic Cancer. www.onclive.com/web-exclusives/Ruxolitinib-Plus-Capecitabine-Improves-Survival-in-Pancreatic-Cancer
13. Haan C, Rolvering C, Raulf F et al. Jak1 has a dominant role over Jak3 in signal transduction through gammac-containing cytokine receptors. Chem. Biol. 18(3), 314-323 (2011)
14. Rodig SJ, Meraz MA, White JM et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93(3), 373-383 (1998).
15. Kiu H, Nicholson SE. Biology and significance of the JAK/ STAT signalling pathways. Growth Factors 30(2), 88-106 (2012).
16. Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU. Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40(1), 52-57 (2004).
17. O'Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat. Rev. Drug Discov. 3(7), 555-564 (2004).
18. Sanda T, Tyner JW, Gutierrez A et al. TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov. 3(5), 564-577 (2013).
19. Prchal-Murphy M, Semper C, Lassnig C et al. TYK2 kinase activity is required for functional type I interferon responses in vivo. PLoS ONE 7(6), e39141 (2012).
20. Dymock BW, See CS. Inhibitors of JAK2 and JAK3: an update on the patent literature 2010-2012. Expert Opin. Ther. Pat. 23(4), 449-501 (2013).
21. Kiss R, Sayeski PP, Keseru GM. Recent developments on JAK2 inhibitors: a patent review. Expert Opin. Ther. Pat. 20(4), 471-495 (2010).
22. Norman P. Selective JAK1 inhibitor and selective Tyk2 inhibitor patents. Expert Opin. Ther. Pat. 22(10), 1233-1249 (2012).
23. Wilson LJ. Recent patents in the discovery of small molecule inhibitors of JAK3. Expert Opin. Ther. Pat. 20(5), 609-623 (2010).
24. Alicea-Velazquez NL, Boggon TJ. The use of structural biology in Janus kinase targeted drug discovery. Curr. Drug Targets 12(4), 546-555 (2011).
25. Hurley CA, Blair WS, Bull RJ et al. Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. Bioorg. Med. Chem. Lett. 23(12), 3592-3598 (2013).
26. Kulagowski JJ, Blair W, Bull RJ et al. Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors. J. Med. Chem. 55(12), 5901-5921 (2012).
27. Zak M, Hurley CA, Ward SI et al. Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2. J. Med. Chem. 56(11), 4764-4785 (2013). • Detailed medicinal chemistry explaining in great detail for the first time the discovery and development of selective JAK1 inhibitors.
28. Flanagan ME, Blumenkopf TA, Brissette WH et al. 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. 53(24), 8468-8484 (2010).
29. Van Rompaey L, Galien R, van der Aar EM et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J. Immunol. 191(7), 3568-3577 (2013).
30. Namour F, Galien R, Gheyle L et al. Once daily high dose regimens of GLPG0634 in healthy volunteers are safe and provide continuous inhibition of JAK1 but not JAK2. Arthritis Rheum. 64(Suppl. 10), 1331 (2012).
31. Schenkel LB, Huang X, Cheng A et al. Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors. J. Med. Chem. 54(24), 8440-8450 (2011).
32. Siu M, Pastor R, Liu W et al. 2-amino-[1,2,4]triazolo[1,5-a] pyridines as JAK2 inhibitors. Bioorg. Med. Chem. Lett. 23(17), 5014-5021 (2013).
33. Dugan BJ, Gingrich DE, Mesaros EF et al. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J. Med. Chem. 55(11), 5243-5254 (2012).
34. Weinberg LR, Albom MS, Angeles TS et al. 2,7-pyrrolo[2,1-f] [1,2,4]triazines as JAK2 inhibitors: modification of target structure to minimize reactive metabolite formation. Bioorg. Med. Chem. Lett. 21(24), 7325-7330 (2011).
35. Zificsak CA, Gingrich DE, Breslin HJ et al. Optimization of a novel kinase inhibitor scaffold for the dual inhibition of JAK2 and FAK kinases. Bioorg. Med. Chem. Lett. 22(1), 133-137 (2012).
36. Labadie S, Barrett K, Blair WS et al. Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors. Bioorg. Med. Chem. Lett. 23(21), 5923-5930 (2013).
37. Siu T, Kozina ES, Jung J et al. The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead. Bioorg. Med. Chem. Lett. 20(24), 7421-7425 (2010).
38. Pissot-Soldermann C, Gerspacher M, Furet P et al. Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors. Bioorg. Med. Chem. Lett. 20(8), 2609-2613 (2010).
39. Hanan EJ, van Abbema A, Barrett K et al. Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors. J. Med. Chem. 55(22), 10090-10107 (2012).
40. Ioannidis S, Lamb ML, Wang T et al. Discovery of 5-chloro-N2-[(1S)-1-(5-luoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)p yrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. J. Med. Chem. 54(1), 262-276 (2011).
41. Hedvat M, Huszar D, Herrmann A et al. The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 16(6), 487-497 (2009).
42. McFarland BC, Ma JY, Langford CP et al. Therapeutic potential of AZD1480 for the treatment of human glioblastoma. Mol. Cancer Ther. 10(12), 2384-2393 (2011).
43. Su Q, Ioannidis S, Chuaqui C et al. Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J. Med. Chem. 57(1), 144-158 (2014).
44. Wang T, Ioannidis S, Almeida L et al. In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg. Med. Chem. Lett. 21(10), 2958-2961 (2011).
45. Harikrishnan LS, Kamau MG, Wan H et al. Pyrrolo[1,2-f] triazines as JAK2 inhibitors: achieving potency and selectivity for JAK2 over JAK3. Bioorg. Med. Chem. Lett. 21(5), 1425-1428 (2011).
46. Ma L, Clayton JR, Walgren RA et al. Discovery and characterization of LY2784544, a small-molecule tyrosine kinase inhibitor of JAK2V617F. Blood Cancer J. 3, e109 (2013).
47. Mitchell D, Cole KP, Pollock PM, Coppert DM, Burkholder TP, Clayton JR. Development and a practical synthesis of the JAK2 inhibitor LY2784544. Org. Process Res. Dev. 16, 70-81 (2012).
48. Shide K, Kameda T, Markovtsov V et al. R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm. Blood 117(25), 6866-6875 (2011).
49. Hart S, Goh KC, Novotny-Diermayr V et al. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia 25(11), 1751-1759 (2011).
50. Madan B, Goh KC, Hart S et al. SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis. J. Immunol. 189(8), 4123-4134 (2012).
51. William AD, Lee AC, Blanchard S et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa- 5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa- 1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/ FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J. Med. Chem. 54(13), 4638-4658 (2011).
52. William AD, Lee AC, Poulsen A et al. Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25- trioxa-19,21,24-triaza-tetracyclo[18. 3.1.1(2,5).1(14,18)] hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis. J. Med. Chem. 55(6), 2623-2640 (2012).
53. Poulsen A, William A, Blanchard S 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(4), 437-450 (2012).
54. Younes A, Romaguera J, Fanale M et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes. J. Clin. Oncol. 30(33), 4161-4167 (2012).
55. Reilly JT. FLT3 and its role in the pathogenesis of acute myeloid leukaemia. Leuk. Lymphoma 44(1), 1-7 (2003).
56. Harrison C, Kiladjian JJ, Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med. 366(9), 787-798 (2012).
57. Verstovsek S, Mesa RA, Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 366(9), 799-807 (2012).
58. Leah E. Clinical trials: Phase III trial results for tofacitinib bring new oral DMARD therapy a step closer for patients with rheumatoid arthritis. Nat. Rev. Rheumatol. 8(10), 561 (2012).
59. Papp KA, Menter A, Strober B et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br. J. Dermatol. 167(3), 668-677 (2012).
60. Vincenti F, Tedesco Silva H, Busque S et al. Randomized Phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am. J. Transplant. 12(9), 2446-2456 (2012).
61. Myrvang H. Transplantation: tofacitinib safe and effective in renal transplant recipients. Nat. Rev. Nephrol. 8(8), 432 (2012).
62. Sandborn WJ, Ghosh S, Panes J et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 367(7), 616-624 (2012).
63. Liew SH, Nichols KK, Klamerus KJ, Li JZ, Zhang M, Foulks GN. Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial. Ophthalmology 119(7), 1328-1335 (2012).
64. Fridman JS, Scherle PA, Collins R et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J. Immunol. 184(9), 5298-5307 (2010).
65. A Study to Test Safety and Efficacy of Baricitinib in Participants With Diabetic Kidney Disease. www.clinicaltrials.gov/ct2/show/NCT01683409
66. Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes. www.clinicaltrials.gov/ct2/show/NCT01724580
67. Minturn JE, Evans AE, Villablanca JG et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother. Pharmacol. 68(4), 1057-1065 (2011).
68. Levis M, Ravandi F, Wang ES et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 117(12), 3294-3301 (2011).
69. Santos FP, Kantarjian HM, Jain N 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(6), 1131-1136 (2010).
70. A Phase 1/2 Study of Oral SB1518 in Subjects With Chronic Idiopathic Myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT00745550
71. SB1518 for Patients With Myelodysplastic Syndrome (MDS), www.clinicaltrials.gov/ct2/show/NCT01436084
72. Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis With Thrombocytopenia (PAC326). www.clinicaltrials.gov/ct2/show/NCT02055781
73. Momelotinib Versus Ruxolitinib in Subjects With Myelofibrosis. www.clinicaltrials.gov/ct2/show/NCT01969838
74. Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia 25(12), 1891-1899 (2011).
75. Tyner JW, Bumm TG, Deininger J et al. CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood 115(25), 5232-5240 (2010).
76. Safety and Efficacy of Momelotinib in Subjects With Polycythemia Vera or Essential Thrombocythemia. www. clinicaltrials.gov/ct2/show/NCT01998828
77. Pardanani A, Gotlib JR, Jamieson C et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J. Clin. Oncol. 29(7), 789-796 (2011).
78. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 22(9), 1790-1792 (2008).
79. Open Label Pharmacokinetic Study of SAR302503 in Subjects With Renal Impairment. www.clinicaltrials.gov/ct2/show/NCT01763190
80. Open Label Pharmacokinetic Study of SAR302503 in Subjects With Hepatic Impairment. www.clinicaltrials.gov/ct2/show/NCT01762462
81. Safety and Preliminary Efficacy of GLPG0634 in Methotrexate-refractory Active Rheumatoid Arthritis Patients. www.clinicaltrials.gov/ct2/show/NCT01384422
82. Two clinical posters on GLPG-0634 (2012). www.glpg.com/index.php/randd/pipeline/glpg0634-ra
83. 24-week Study With Open Label Extension of VX-509, an Oral JAK3 Inhibitor, in Subjects Taking Methotrexate. www.clinicaltrials.gov/ct2/show/NCT01590459
84. A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Doses of GSK2586184 and the Effect of Food and Gender (JAK116439). www.clinicaltrials.gov/ct2/show/NCT01687309
85. A Study of LY2784544 in Participants With Myeloproliferative Neoplasms. www.clinicaltrials.gov/ct2/show/NCT01594723
86. Xin H, Herrmann A, Reckamp K et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res. 71(21), 6601-6610 (2011).
87. Study to Assess Safety, Tolerability and PK of AZD1480 in Patients With Solid Tumours. www.clinicaltrials.gov/ct2/show/NCT01112397
88. Multiple Ascending Dose of BMS-911543. www.clinicaltrials.gov/ct2/show/NCT01236352
89. Purandare AV, McDevitt TM, Wan H et al. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia 26(2), 280-288 (2012).
90. Nakaya Y, Shide K, Niwa T et al. Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms. Blood Cancer J. 1(7), e29 (2011).
91. Safety and Tolerability Study of Oral NS-018 in Patients With Primary Myelofibrosis (MF), Post-polycythemia Vera MF or Post-essential Thrombocythemia MF. www.clinicaltrials.gov/ct2/show/NCT01423851
92. A Safety Study of XL019 in Adults With Myelofibrosis. www. clinicaltrials.gov/ct2/show/NCT00522574
93. A Phase 1 Study of XL019 in Adults With Polycythemia Vera. www.clinicaltrials.gov/ct2/show/NCT00595829
94. A Single and Multiple-Dose Study of SB1578. www.clinicaltrials.gov/ct2/show/NCT01235871
95. An Open Label Study of INCB039110 Administered Orally in Patients With Myelofibrosis. www.clinicaltrials.gov/show/NCT01633372
96. First-in-Human Study to Evaluate Safety and Tolerability of Single and Multiple Ascending Doses of Janus Kinase-1 Inhibitor PF-04965842 in Healthy Western and Japanese Subjects. www.clinicaltrials.gov/ct2/show/NCT01835197
97. A Phase 1 Study To Evaluate Tolerability, Safety, And Pharmacokinetics Of Topical PF-06263276 In Healthy Subjects. www.clinicaltrials.gov/ct2/show/NCT01981681
98. Forsyth T, Kearney PC, Kim BG et al. SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg. Med. Chem. Lett. 22(24), 7653-7658 (2012).
99. Lim J, Taoka B, Otte RD et al. Discovery of 1-amino-5H- pyrido[4,3-b]indol-4-carboxamide inhibitors of Janus kinase 2 (JAK2) for the treatment of myeloproliferative disorders. J. Med. Chem. 54(20), 7334-7349 (2011).
100. Kraus M, Wang Y, Aleksandrowicz D et al. Efficacious intermittent dosing of a novel JAK2 inhibitor in mouse models of polycythemia vera. PLoS ONE 7(5), e37207 (2012).
101. Nakaya Y, Shide K, Naito H et al. Effect of NS-018, a selective JAK2V617F inhibitor, in a murine model of myelofibrosis. Blood Cancer J. 4, e174 (2014).
102. Wang T, Ledeboer MW, Duffy JP et al. A novel chemotype of kinase inhibitors: discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors. Bioorg. Med. Chem. Lett. 20(1), 153-156 (2010).
103. Li MY, Tian Y, Shen L et al. 3-O-methylthespesilactam, a new small-molecule anticancer pan-JAK inhibitor against A2058 human melanoma cells. Biochem. Pharmacol. 86(10), 1411-1418 (2013).
104. Liu L, Nam S, Tian Y et al. 6-bromoindirubin-3'-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells. Cancer Res. 71(11), 3972-3979 (2011).
105. Andraos R, Qian Z, Bonenfant D et al. Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent. Cancer Discov. 2(6), 512-523 (2012). • Outstanding work by Novartis to identify the first type II JAK2 inhibitor and demonstrate the importance of activation loop phosphorylation.
106. Baffert F, Regnier CH, De Pover A et al. Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. Mol. Cancer Ther. 9(7), 1945-1955 (2010).
107. Lin TH, Hegen M, Quadros E et al. Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice. Arthritis Rheum. 62(8), 2283-2293 (2010).
108. Thoma G, Nuninger F, Falchetto R et al. Identification of a potent Janus kinase 3 inhibitor with high selectivity within the Janus kinase family. J. Med. Chem. 54(1), 284-288 (2011).
109. Soth M, Hermann JC, Yee C et al. 3-amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. J. Med. Chem. 56(1), 345-356 (2013). • Rare description of a JAK3-selective inhibitor.
110. Tanaka N, Asao H, Ohbo K et al. Physical association of JAK1 and JAK2 tyrosine kinases with the interleukin 2 receptor beta and gamma chains. Proc. Natl Acad. Sci. USA 91(15), 7271-7275 (1994).
111. Koresawa M, Okabe T. High-throughput screening with quantitation of ATP consumption: a universal non- radioisotope, homogeneous assay for protein kinase. Assay Drug Dev. Technol. 2(2), 153-160 (2004).
112. Liang J, Tsui V, Van Abbema A et al. Lead identification of novel and selective TYK2 inhibitors. Eur J. Med. Chem. 67, 175-187 (2013).
113. Abad-Zapatero C, Metz JT. Ligand efficiency indices as guideposts for drug discovery. Drug Discov. Today 10(7), 464-469 (2005).
114. Hopkins AL, Groom CR, Alex A. Ligand efficiency: a useful metric for lead selection. Drug Discov. Today 9(10), 430-431 (2004).
115. Kuntz ID, Chen K, Sharp KA, Kollman PA. The maximal affinity of ligands. Proc. Natl Acad. Sci. USA 96(18), 9997-10002 (1999).
116. Oprea TI, Davis AM, Teague SJ, Leeson PD. Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci. 41(5), 1308-1315 (2001).
117. Wenlock MC, Austin RP, Barton P, Davis AM, Leeson PD. A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 46(7), 1250-1256 (2003).
118. Sohn SJ, Barrett K, Van Abbema A et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J. Immunol. 191(5), 2205-2216 (2013). • Detailed, in-depth description of a selective TYK2 inhibitor from Genentech.
119. Liang J, van Abbema A, Balazs M et al. Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors. J. Med. Chem. 56(11), 4521-4536 (2013).
120. Paulini R, Muller K, Diederich F. Orthogonal multipolar interactions in structural chemistry and biology. Angew. Chem. Int. Ed. Engl. 44(12), 1788-1805 (2005).
121. Chrencik JE, Patny A, Leung IK 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(3), 413-433 (2010). • Crystallography studies of TYK2, revealing the importance of activation loop dynamics, the 'His - Asp loop lock', through inhibitor binding.
122. Koppikar P, Bhagwat N, Kilpivaara O et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature 489(7414), 155-159 (2012). • Highly impacting elegant studies of the mechanisms behind JAK - STAT pathway reactivation following JAK inhibitor treatment.
123. Hurwitz H. Abstract #4000Presented at: 2014 ASCO Annual Meeting. Chicago, IL, USA, 30 May-3 June 2014. www.healio.com/hematology-oncology/highlights-from-asco-2014/ruxolitinib-plus-capecitabine-extended-survival-in-metastatic-pancreatic-cancer
124. Panobinostat and Ruxolitinib In MyElofibrosis (PRIME Trial). www.clinicaltrials.gov/show/NCT01693601
125. Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia. www.clinicaltrials.gov/ct2/show/NCT01914484
126. A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF. www.clinicaltrials.gov/ct2/show/NCT01787552
127. Phase I Study of the Combination of Afatinib and Ruxolitinib in Patients With Treatment-refractory Non- Small Cell Lung Cancer (NSCLC). www.clinicaltrials.gov/ct2/show/NCT02145637
128. Novotny-Diermayr V, Hart S, Goh KC et al. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. Blood Cancer J. 2(5), e69 (2012)
129. Waibel M, Solomon VS, Knight DA et al. Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2- driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep. 5(4), 1047-1059 (2013).
130. EMA. Xeljanz. www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002542/smops/Negative/human-smop-000501.jsp&mid=WC0b01ac058001d127
131. Baxter and Cell Therapeutics Announce Worldwide Strategic Collaboration to Develop and Commercialize Pacritinib. http://www.baxter.com/press-room/press-releases/2013/11-15-13-pacritinib.html future
132. Cell Therapeutics Announces Agreement with the FDA on Special Protocol Assessment for Planned Pivotal Phase 3 Trial of Pacritinib in Myelofibrosis. http://www.bloomberg.com/article/2013-10-07/atwWW6Jq.5xU.html
133. Sanofi pulls plug on fedratinib over brain disorder risk. www.pharmatimes.com/article/13-11-18/Sanofi-pulls-plug-on-fedratinib-over-brain-disorder-risk.aspx
134. Gilead Sciences to Acquire YM BioSciences. www.investors.gilead.com/phoenix.zhtml?c=69964&p=irol-newsArticle&ID=1766528&highlight