title: New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
abstract: Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ujunwa C
authors.initials: UC
authors.lastname: Okoye-Okafor
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jessy
authors.initials: J
authors.lastname: Cartier
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Enoch N
authors.initials: EN
authors.lastname: Gao
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Pietrak
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Rominger
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Quinn
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wiggall
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Reif
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Schmidt
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Huizhen
authors.identifier: http://orcid.org/0000-0002-6742-8656
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Cellzome, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Faelth-Savitski
authors.affiliation: Cellzome, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.affiliation: Cellzome, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Chaya
authors.initials: C
authors.lastname: Duraiswami
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: Brady
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Groy
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Swathi-Rao
authors.initials: SR
authors.lastname: Narayanagari
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Iléana
authors.initials: I
authors.lastname: Antony-Debre
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mitchell
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Heng Rui
authors.initials: HR
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yun-Ruei
authors.initials: YR
authors.lastname: Kao
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center, Hamburg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Christopeit
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvajal
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Barreyro
authors.affiliation: Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, New York, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Will
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Nestor
authors.initials: N
authors.lastname: Concha
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Adams
authors.affiliation: Department of Molecular Discovery Research, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, New York, USA.|Department of Developmental &Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.|Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.|Division of Hemato-Oncology, Department of Medicine (Oncology), Albert Einstein College of Medicine / Montefiore Medical Center, Bronx, New York, USA.|Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York, USA.|Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D018899:CpG Islands; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004095:Dihydropyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D003596:Cytosine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human