BAY-1436032

BAY-1436032 (BAY1436032) is a potent, selective, orally available inhibitor of pan-mutant IDH1 with IC50 of 15 nM for both IDH1 R132H and R132C, respectively; shows no effect on wild-type IDH1; strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations; significantly prolongs survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation.Blood Cancer Phase 1 Clinical(In Vitro):BAY-1436032 is a novel pan-mutant isocitrate dehydrogenase 1 (IDH1) inhibitor. BAY-1436032 inhibits intracellular (R)-2-hydroxyglutarate (R-2HG) production in mouse hematopoietic cells expressing IDH1R132H or IDH1R132C with IC50s of 60 and 45 nM, respectively. R-2HG levels are not reduced in IDH2R140Q and IDH2R172K expressing mouse hematopoietic cells by BAY-1436032 at concentrations up to 10 μM. Colony growth is inhibited by 50% at a concentration of 0.1 μM BAY-1436032, while concentrations up to 100 μM do not suppress colony growth of patient-derived IDH1 wild-type AML cells. On morphologic evaluation myelomonocytic differentiation of myeloid progenitors is strongly induced by BAY-1436032.\n(In Vivo):Long-term exposure to once daily oral BAY-1436032 reveals nearly complete suppression of (R)-2-hydroxyglutarate (R-2HG) production with 150 mg/kg BAY1436032. White blood cell counts constantly increase in vehicle-treated mice and, at a lower rate, in animals receiving 45 mg/kg BAY-1436032, while they remain constant in the 150 mg/kg cohort. Hemoglobin levels are slightly lower in the vehicle and 45 mg/kg groups as compare to the 150 mg/kg cohort at day 60, while platelet counts are significantly reduced in vehicle and 45 mg/kg BAY-1436032 treated mice compare to the 150 mg/kg cohort at day 60. All mice receiving 150 mg/kg BAY-1436032 survive with minimal hCD45+ cell load in their peripheral blood until the end of observation at day 150 after treatment start (P<0.001), while vehicle-treated animals die from leukemia with a median survival of 91 days. Mice treated with 45 mg/kg BAY-1436032 display intermediate levels of CD14/CD15 expression.