BAY-1436032 is a novel, selective and orally available inhibitor of pan-mutant isocitrate dehydrogenase 1 (IDH1).

BAY-1436032在表达IDH1R132H或IDH1R132C的小鼠造血细胞中抑制（R）-2-羟基戊二酸（R-2HG）的内部生成（IC50s：60和45nM）。在表达IDH2R140Q和IDH2R172K的小鼠造血细胞中，BAY-1436032即使浓度高达10μM也不会减少R-2HG水平。0.1μM BAY-1436032可以抑制集落生长50%，而高达100μM的浓度对源自患者的IDH1野生型AML细胞的集落生长则无抑制作用。形态学评估显示，BAY-1436032强烈诱导骨髓源性前体细胞的髓-单核细胞分化。

长期每日一次口服BAY-1436032的研究显示，以150mg/kg的剂量几乎完全抑制了R-2HG的产生。在仅接受载体处理的小鼠中，白细胞计数持续增加，而接受45mg/kg BAY-1436032治疗的动物白细胞增加速度较低；然而，在接受150mg/kg剂量治疗的组别中，白细胞计数保持不变。与接受车载体和45mg/kg剂量治疗的组别相比，接受150mg/kg剂量治疗的小鼠在治疗后第60天的血红蛋白水平略低，而血小板计数显著减少。接受150mg/kg BAY-1436032治疗的所有小鼠，在治疗开始后的第150天观察期结束时，周围血液中的hCD45+细胞负担最小，全部存活；而仅接受载体处理的动物因白血病死亡，中位生存期为91天。接受45mg/kg BAY-1436032治疗的小鼠显示CD14/CD15表达的中等水平。

Colony-forming cell (CFC) units are assayed in methylcellulose supplemented with 10?ng/mL IL-3, 10?ng/mL GM-CSF, 50?ng/ mL SCF, 50?ng/mL FLT3-ligand and 3?U/mL EPO. Vehicle or BAY-1436032 is added to methylcellulose containing 1 × 10^5 human mononuclear cells, which are plated in duplicate. Colonies are evaluated microscopically 10 to 14 days after plating by standard criteria.

NSG mice are used and transplanted with primary acute myeloid leukemia (AML) cells from a patient with IDH1R132C mutant AML. Per condition 10 mice are treated with vehicle, 45 or 150?mg/kg body weight BAY-1436032 once daily by oral gavage for 150 days starting 17 days after transplantation. Finally, serum R-2HG levels and human CD45+ (hCD45+) cells are measured.