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Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo

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 nov...

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Main Authors: Chaturvedi, Anuhar (Author) , Pusch, Stefan (Author) , Stichel, Damian (Author) , Bochtler, Tilmann (Author) , Ho, Anthony Dick (Author) , Deimling, Andreas von (Author) , Rippe, Karsten (Author) , Krämer, Alwin (Author)
Format: Article (Journal)
Language:English
Published: 24 February 2017
In: Leukemia
Year: 2017, Volume: 31, Issue: 10, Pages: 2020-2028
ISSN:1476-5551
DOI:10.1038/leu.2017.46
Online Access:Verlag, Volltext: http://dx.doi.org/10.1038/leu.2017.46
Verlag, Volltext: https://www.nature.com/leu/journal/vaop/ncurrent/full/leu201746a.html
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Author Notes:A. Chaturvedi, L. Herbst, S. Pusch, L. Klett, R. Goparaju, D. Stichel, S. Kaulfuss, O. Panknin, K. Zimmermann, L. Toschi, R. Neuhaus, A. Haegebarth, H. Rehwinkel, H. Hess-Stumpp, M. Bauser, T. Bochtler, E.A. Struys, A. Sharma, A. Bakkali, R. Geffers, M.M. Araujo-Cruz, F. Thol, R. Gabdoulline, A. Ganser, A.D. Ho, A. von Deimling, K. Rippe, M. Heuser and A. Krämer
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Summary: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.
Item Description:Gesehen am 15.11.2017
Physical Description:Online Resource
ISSN:1476-5551
DOI:10.1038/leu.2017.46

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