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Ref Type Journal Article
PMID (28232670)
Authors Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, Kaulfuss S, Panknin O, Zimmermann K, Toschi L, Neuhaus R, Haegebarth A, Rehwinkel H, Hess-Stumpp H, Bauser M, Bochtler T, Struys EA, Sharma A, Bakkali A, Geffers R, Araujo-Cruz MM, Thol F, Gabdoulline R, Ganser A, Ho AD, von Deimling A, Rippe K, Heuser M, Krämer A
Title Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.
Journal Leukemia
Vol 31
Issue 10
Date 2017 10
URL
Abstract Text 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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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BAY1436032 BAY1436032 5 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY1436032 IDH1 Inhibitor 8 BAY1436032 inhibits mutant IDH1, resulting in decreased levels of (R)-2-hydroxyglutarate (R-2HG) and leading to reduced proliferation and increased differentiation of IDH1-mutant tumor cells (PMID: 28232670).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132C acute myeloid leukemia sensitive BAY1436032 Preclinical - Pdx & cell culture Actionable In a preclinical study, BAY1436032 decreased R-2HG levels and inhibited growth of primary acute myeloid leukemia (AML) cells harboring IDH1 R132C in culture, and decreased blast number and increased survival of two AML patient-derived xenograft (PDX) models, one which harbored additional alterations in FLT3, NPM1, and NRAS and one which harbored a KMT2A (MLL) alteration (PMID: 28232670). 28232670
IDH1 R132L acute myeloid leukemia sensitive BAY1436032 Preclinical - Patient cell culture Actionable In a preclinical study, BAY1436032 decreased (R)-2-hydroxyglutarate (R-2HG) levels, and inhibited growth and increased differentiation of patient-derived acute myeloid leukemia cells harboring IDH1 R132L in culture (PMID: 28232670). 28232670
IDH1 R132S acute myeloid leukemia sensitive BAY1436032 Preclinical - Patient cell culture Actionable In a preclinical study, BAY1436032 decreased (R)-2-hydroxyglutarate (R-2HG) levels, and inhibited growth and increased differentiation of patient-derived acute myeloid leukemia cells harboring IDH1 R132S in culture (PMID: 28232670). 28232670
IDH1 R132G acute myeloid leukemia sensitive BAY1436032 Preclinical - Patient cell culture Actionable In a preclinical study, BAY1436032 decreased (R)-2-hydroxyglutarate (R-2HG) levels and increased differentiation of patient-derived acute myeloid leukemia cells harboring IDH1 R132G in culture (PMID: 28232670). 28232670
IDH1 R132H acute myeloid leukemia sensitive BAY1436032 Preclinical - Patient cell culture Actionable In a preclinical study, BAY1436032 decreased (R)-2-hydroxyglutarate (R-2HG) levels, and inhibited growth and increased differentiation of patient-derived acute myeloid leukemia cells harboring IDH1 R132H in culture (PMID: 28232670). 28232670