title: Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo.
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.
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Krausert
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Fischer
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Balss
authors.affiliation: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Neurology Clinic and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ott
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schrimpf
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Eisel
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Beck
authors.affiliation: Core Facility, Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.affiliation: Core Facility, Small Animal Imaging Center, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Eichwald
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaulfuss
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Panknin
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rehwinkel
authors.affiliation: Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Roman C
authors.initials: RC
authors.lastname: Hillig
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Guenther
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Luisella
authors.initials: L
authors.lastname: Toschi
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haegebart
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bauser
authors.affiliation: Neurology Clinic and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Neurology Clinic and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. andreas.vondeimling@med.uni-heidelberg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001254:Astrocytoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004926:Escherichia coli; D005260:Female; D005977:Glutarates / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D061987:Sf9 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000622445:BAY 1436032; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005977:Glutarates; D011994:Recombinant Proteins; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Drug development; IDH-mutated glioma; IDH1R132 inhibitor; Mouse xenograft; Pharmacology; Therapy