title: Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.
abstract: A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.forename: Byron
authors.initials: B
authors.lastname: DeLaBarre
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schalm
authors.forename: Erica
authors.initials: E
authors.lastname: Hansen
authors.forename: Kimberly
authors.initials: K
authors.lastname: Straley
authors.forename: Andrew
authors.initials: A
authors.lastname: Kernytsky
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Camelia
authors.initials: C
authors.lastname: Gliser
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.forename: Erin
authors.initials: E
authors.lastname: Artin
authors.forename: Veronique
authors.initials: V
authors.lastname: Saada
authors.forename: Elena
authors.initials: E
authors.lastname: Mylonas
authors.forename: Cyril
authors.initials: C
authors.lastname: Quivoron
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.forename: Jeffrey O
authors.initials: JO
authors.lastname: Saunders
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Stuart
authors.initials: S
authors.lastname: Murray
authors.forename: Wentao
authors.initials: W
authors.lastname: Wei
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.forename: Sam
authors.initials: S
authors.lastname: Agresta
authors.forename: David P
authors.initials: DP
authors.lastname: Schenkein
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.forename: Stephane
authors.initials: S
authors.lastname: de Botton
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
mesh_terms: D000495:Allosteric Site; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004920:Erythropoiesis / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D005977:Glutarates / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010671:Phenylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017354:Point Mutation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C581155:AGI-6780; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005977:Glutarates; D050505:Mutant Proteins; D010671:Phenylurea Compounds; D054852:Small Molecule Libraries; D013449:Sulfonamides; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase