生物活性

• 描述The Janus kinases (JAK) are a class of non-receptor tyrosine kinases essential for cytokine signal transduction via the JAK/STAT pathway. BMS-911543 is a potent, selective inhibitor of JAK2 with an IC50 value of 1.1 nM. The dissociation constant (K_i) values of BMS-911543 for JAK1, JAK2 and JAK3 are 1114, 0.48 and 357 nM, respectively. BMS-911543 displayed a dose-dependent anti-proliferative effect in JAK2^V617F-dependent cells such as SET2 and Ba/F3 with IC50 values of 60 and 70 nM, respectively. In Ba/F^JAK2V617F cells, BMS-911543 treatment resulted in dose-dependent reduction of pSTAT5 with an IC50 value of 60 nM. In human whole-blood ex vivo assay, BMS-911543 dose-dependently inhibited TPO-stimulated pSTAT5 in human platelets. In primary hematopoetic CD34⁺ progenitors isolated from normal healthy volunteers, BMS-911543 inhibited EPO-mediated burst forming unit-erythroid (BFU-E) colony growth with an IC50 of approximately 1.5 μM. In cells isolated from JAK2^V617F-positive MPN patient, BMS-911543 inhibited BFU-E with an IC50 of 0.3 μM in the presence of EPO compared with an IC50 of 0.075 μM in EPO-independent erythroid colony formation. A single oral dose of 30 mg/kg BMS-911543 in PD-PK mouse model fully inhibited pSTAT5 induction at 1 – 18h post treatment. In athymic mice xenografted with SET2 cells, 10 mg/kg BMS-911543 demonstrated 90 – 100% pSTAT5 inhibition up to 7h post dose. In a mouse model of antigen-induced antibody production, BMS-911543 at 10 and 30 mg/kg resulted in 65% and 85% reduction, respectively, in the level of IgG antibody^[4].
• 作用机制BMS-911543 is a selective ATP-competitive inhibitor of JAK2^[4].

• 动物研究
  剂量	Mice: 3 mg/kg - 30 mg/kg[3] (p.o.); 2 mg/kg[1] (i.v.) Rat: 1 mg/kg[1] (i.v./p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Monkeys[1] Dose 2.0 mg/kg (i.v.) 10 mg/kg (p.o.) 1.0 mg/kg (i.v.) 1.0 mg/kg (p.o.) 0.2 mg/kg (i.v.) 0.2 mg/kg (p.o.) 1.0 mg/kg (i.v.) 1.0 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. i.v. p.o. F 1 1 0.82 0.53 T1/2 5.1 h 5 h 2.2 h 2.4 h CL 0.55 ml/min/kg 0.7 ml/min/kg 6.5 ml/min/kg 5.3 ml/min/kg Vss 0.26 L/kg 0.3 L/kg 1.6 L/kg 1.1 L/kg

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01236352	Cancer	Phase 1 Phase 2	Completed	-	United States, Minnesota ... more >> Mayo Clinic Rochester, Minnesota, United States, 55905 United States, New York The Mount Sinai School Of Medicine New York, New York, United States, 10029 United States, Texas The University Of Texas Md Anderson Cancer Center Houston, Texas, United States, 77030 Australia, Victoria Local Institution East Melbourne, Victoria, Australia, 3002 Local Institution Melbourne, Victoria, Australia, 3050 Collapse <<

• 参考文献

• [1] Wan H, Schroeder GM, et al. Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms. ACS Med Chem Lett. 2015 Jul 12;6(8):850-5.

  [2] Purandare AV, McDevitt TM, et al. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8.

  [3] Pomicter AD, Eiring AM, et al. Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm. Exp Hematol. 2015 Jul;43(7):537-45.e1-11.

  [4] Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, Lombardo L, Pedicord D, Gottardis MM, Ross-Macdonald P, de Silva H, Hosbach J, Emanuel SL, Blat Y, Fitzpatrick E, Taylor TL, McIntyre KW, Michaud E, Mulligan C, Lee FY, Woolfson A, Lasho TL, Pardanani A, Tefferi A, Lorenzi MV. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8.