Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
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We acknowledge assistance of the Cell Sorting Core Facility of Hannover Medical School supported in part by the Braukmann–Wittenberg–Herz–Stiftung and the Deutsche Forschungsgemeinschaft. We thank all participating patients and contributing doctors, the staff of the Central Animal Facilities of Hannover Medical School and German Cancer Research Center (DKFZ), and R. Schottmann, K. Görlich, S. Glowotz, M. Wichmann, J. Eisel and S. Schumacher for support. This work was supported by grants from the DKFZ-Bayer Alliance, an ERC grant under the European Union’s Horizon 2020 research and innovation programme (No. 638035), by grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung e.V; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); DFG grants KR1981/4-1, HE5240/5-1 and HE5240/6-1; grants from Wilhelm Sander-Stiftung, Dieter-Schlag Stiftung, a HiLF grant from Hannover Medical School awarded to AC, and a Stiftung für Krebs- und Scharlachforschung Mannheim grant to LH.
AK, MH, AC and LH conceived and designed the study; AC, LH, SP, LK, RG, DS, SK, TB, EAS, AS, AB, RG, MMA-C, FT, RG, AG, ADH, AD, KR, MH and AK collected, analyzed, and assembled the data; OP, KZ, LT, RN, AH, HR, HH-S and MB provided critical reagents; AK and MH wrote the manuscript; and all authors reviewed the data, and edited and approved the final version of the manuscript.
MH received research support from Bayer. The remaining authors declare no conflict of interest.
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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, 2020–2028 (2017). https://doi.org/10.1038/leu.2017.46
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