BAY-1436032, identified as a comprehensive mutant IDH1 inhibitor, curtails the production of intracellular (R)-2-hydroxyglutarate (R-2HG) in mouse hematopoietic cells harboring IDH1R132H or IDH1R132C mutations, with IC50s of 60 and 45 nM, respectively. It does not affect R-2HG levels in cells expressing IDH2R140Q and IDH2R172K up to a concentration of 10 μM. A 0.1 μM concentration of BAY-1436032 inhibits colony growth by 50%, while up to 100 μM does not hinder the colony growth of AML cells with wild-type IDH1. BAY-1436032 notably induces myelomonocytic differentiation in myeloid progenitors[1].
BAY-1436032 动物研究
Animal study
Chronic oral administration of BAY-1436032 results in almost complete inhibition of (R)-2-hydroxyglutarate (R-2HG) production at a dose of 150 mg/kg. White blood cell counts rise continuously in control mice and to a lesser extent in those treated with 45 mg/kg BAY-1436032, but remain stable in the 150 mg/kg group. Hemoglobin levels are marginally lower in the control and 45 mg/kg groups compared to the 150 mg/kg group at day 60, while platelet counts are significantly lower in the control and 45 mg/kg groups than in the 150 mg/kg group at the same time point. All mice treated with 150 mg/kg BAY-1436032 survive with minimal hCD45+ cells in their blood until day 150 post-treatment, whereas control mice succumb to leukemia with a median survival of 91 days. Mice receiving 45 mg/kg BAY-1436032 show intermediate CD14/CD15 expression levels[1].
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