title: Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.
abstract: 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.
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Chaturvedi
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Herbst
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: S
authors.identifier: 0000-0002-3407-4249
authors.initials: S
authors.lastname: Pusch
authors.affiliation: Research Group Genome Organization &Function, German Cancer Research Center (DKFZ) and Bioquant Center, Heidelberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Klett
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Goparaju
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Stichel
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kaulfuss
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Panknin
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Toschi
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Haegebarth
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Rehwinkel
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Hess-Stumpp
authors.affiliation: Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bauser
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bochtler
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E A
authors.initials: EA
authors.lastname: Struys
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Bakkali
authors.affiliation: Genome Analysis, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Araujo-Cruz
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gabdoulline
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: A D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Research Group Genome Organization &Function, German Cancer Research Center (DKFZ) and Bioquant Center, Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rippe
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Krämer
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005977:Glutarates / Q000378:metabolism; D042421:Histone Code / Q000187:drug effects; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008745:Methylation / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D020125:Mutation, Missense; D022423:Myeloid Cells / Q000187:drug effects; D038042:Myelopoiesis / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000622445:BAY 1436032; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005977:Glutarates; D009363:Neoplasm Proteins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human