BAY-1436032

BAY-1436032 is an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1; IC₅₀ = 0.015 µM for both IDH1^R132H and IDH1^R132C).¹ It is selective for mutant IDH1 over wild-type IDH1 and IDH2 (IC₅₀s = 20 and >100 µM, respectively). BAY-1436032 inhibits production of α-hydroxyglutaric acid (2-HG; Item Nos. 25894 | 16374) in HEK293 cells expressing IDH1^R132H, IDH1^R132C, IDH1^R132G, IDH1^R132S, and IDH1^R132L, but not IDH1^R100Q, IDH2^R172K, IDH2^R172W, or IDH2^R172M. It also inhibits 2-HG production in LN-229 glioblastoma and HCT116 colorectal carcinoma cells overexpressing IDH1^R132H (IC₅₀s = 73 and 47 nM, respectively), as well as in HT-1080 sarcoma cells endogenously expressing IDH1^R132C (IC₅₀ = 135 nM). BAY-1436032 (150 mg/kg) reduces tumor growth and increases survival in an NCH551b IDH1^R132H mutant secondary glioblastoma patient-derived xenograft (PDX) mouse model. It also induces myeloid differentiation of IDH1^R132C mutant acute myeloid leukemia (AML) cells in mice when administered at doses of 45 and 150 mg/kg.²

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1. Pusch, S., Krausert, S., Fischer, V., et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol. 133(4), 629-644 (2017).

2. Chaturvedi, A., Herbst, L., Pusch, S., et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia 31(10), 2020-2028 (2017).