title: Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
abstract: A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.
authors.forename: Stuart
authors.initials: S
authors.lastname: Jones
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ahmet
authors.forename: Kelly
authors.initials: K
authors.lastname: Ayton
authors.affiliation: Manchester Institute of Biotechnology, University of Manchester , Princess Street, Manchester, M1 7DN, U.K.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ball
authors.forename: Mark
authors.initials: M
authors.lastname: Cockerill
authors.forename: Emma
authors.initials: E
authors.lastname: Fairweather
authors.forename: Nicola
authors.initials: N
authors.lastname: Hamilton
authors.forename: Paul
authors.initials: P
authors.lastname: Harper
authors.forename: James
authors.initials: J
authors.lastname: Hitchin
authors.forename: Allan
authors.identifier: 0000-0003-3449-3993
authors.initials: A
authors.lastname: Jordan
authors.affiliation: Manchester Institute of Biotechnology, University of Manchester , Princess Street, Manchester, M1 7DN, U.K.
authors.forename: Colin
authors.initials: C
authors.lastname: Levy
authors.affiliation: Manchester Institute of Biotechnology, University of Manchester , Princess Street, Manchester, M1 7DN, U.K.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lopez
authors.affiliation: Manchester Institute of Biotechnology, University of Manchester , Princess Street, Manchester, M1 7DN, U.K.
authors.forename: Eddie
authors.initials: E
authors.lastname: McKenzie
authors.forename: Martin
authors.initials: M
authors.lastname: Packer
authors.forename: Darren
authors.initials: D
authors.lastname: Plant
authors.forename: Iain
authors.initials: I
authors.lastname: Simpson
authors.forename: Peter
authors.initials: P
authors.lastname: Simpson
authors.forename: Ian
authors.initials: I
authors.lastname: Sinclair
authors.forename: Tim C P
authors.initials: TC
authors.lastname: Somervaille
authors.forename: Helen
authors.initials: H
authors.lastname: Small
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Spencer
authors.forename: Graeme
authors.initials: G
authors.lastname: Thomson
authors.forename: Michael
authors.initials: M
authors.lastname: Tonge
authors.forename: Ian
authors.initials: I
authors.lastname: Waddell
authors.forename: Jarrod
authors.initials: J
authors.lastname: Walsh
authors.forename: Bohdan
authors.identifier: 0000-0001-8572-2018
authors.initials: B
authors.lastname: Waszkowycz
authors.forename: Mark
authors.initials: M
authors.lastname: Wigglesworth
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wiseman
authors.forename: Donald
authors.initials: D
authors.lastname: Ogilvie
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human