BMS-911543

A potent and selective small-molecule inhibitor of JAK2 with IC50 of 1.1 nM; displays 350-, 75- and 65-fold selective to JAK1, JAK3 and TYK2, respectively; displays anti-proliferative effect on JAK2 (V617F) MPNs and inhibits pSTAT5 in Ba/FJAK2V617F cells (IC50=60 nM) ; highly active in in vivo models and orally bioactive.Bone Cancer Phase 1 Clinical (In Vitro) :BMS-911543 is a selective JAK2 inhibitor, with IC50s of 1.1 nM, less selective at JAK1, JAK3 and TYK2 (IC50, 75, 360, 66 nM, respectively) . BMS-911543 displays IC50 of >25 μM for all targets except PDE4 (IC50, 5.6 μM) . BMS-911543 exhibits potent antiproliferative effect on the SET-2 and BaF3-V617F engineered cell lines (both dependent upon JAK2 pathway), with IC50s of 60 and 70 nM, respectively, and such an effect on SET-2 and BaF3-V617F cells is correlated with similar activity on constitutively active pSTAT5 (IC50, 80 and 65 nM, respectively) . BMS-911543 (>20 μM) is cytotoxic to murine or human pancreatic ductal adenocarcinoma (PDAC) cell lines. BMS-911543 (5 and 10 μM) also blocks T regulatory cell differentiation in vitro. (In Vivo) :BMS-911543 is well tolerated up to 100 mg/kg in rats (mean AUC0-72 h, 11300 μM·h) and dogs (AUC0-24 h, 610 μM·h) . A 15 mg/kg/day dose (Day 14 AUC0-24 h, 3200 μM·h) is well tolerated in two-week repeat dose studies in rats. BMS-911543 (30 mg/kg, p.o.) suppresses the growth of tumor and prolongs the median survival in KPC-Brca1 mice. BMS-911543 also selectively reduces pSTAT5 expression in pancreatic tumors and decreases levels of intratumoral FoxP3+ T regulatory cells in mice administered BMS-911543.