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01-04-2017 | Original Paper

Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo

Authors: Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C. Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling

Published in: Acta Neuropathologica | Issue 4/2017

Abstract

Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular d-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.

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Title: Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo
Authors: Stefan Pusch
Sonja Krausert
Viktoria Fischer
Jörg Balss
Martina Ott
Daniel Schrimpf
David Capper
Felix Sahm
Jessica Eisel
Ann-Christin Beck
Manfred Jugold
Viktoria Eichwald
Stefan Kaulfuss
Olaf Panknin
Hartmut Rehwinkel
Katja Zimmermann
Roman C. Hillig
Judith Guenther
Luisella Toschi
Roland Neuhaus
Andrea Haegebart
Holger Hess-Stumpp
Markus Bauser
Wolfgang Wick
Andreas Unterberg
Christel Herold-Mende
Michael Platten
Andreas von Deimling
Publication date: 01-04-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1677-y

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Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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