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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	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	31	10	2017 10	2020-2028	Leukemia

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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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Molecular Profile	Treatment Approach
IDH1 R132C	IDH1 Inhibitor
IDH1 R132H	IDH1 Inhibitor
IDH1 R132I	IDH1 Inhibitor
IDH1 R132L	IDH1 Inhibitor
IDH1 R132P	IDH1 Inhibitor
IDH1 R132S	IDH1 Inhibitor
IDH1 R132V	IDH1 Inhibitor
IDH1 R132X	IDH1 Inhibitor

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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
BAY1436032	BAY1436032	8	2

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BAY1436032		BAY-1436032\|BAY 1436032	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, PMID: 32733012).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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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 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
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

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