2. Academic Validation
  3. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation

Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation

  • Science. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769.
Fang Wang 1,  Jeremy Travins,  Byron DeLaBarre,  Virginie Penard-Lacronique,  Stefanie Schalm,  Erica Hansen,  Kimberly Straley,  Andrew Kernytsky,  Wei Liu,  Camelia Gliser,  Hua Yang,  Stefan Gross,  Erin Artin,  Veronique Saada,  Elena Mylonas,  Cyril Quivoron,  Janeta Popovici-Muller,  Jeffrey O Saunders,  Francesco G Salituro,  Shunqi Yan,  Stuart Murray,  Wentao Wei,  Yi Gao,  Lenny Dang,  Marion Dorsch,  Sam Agresta,  David P Schenkein,  Scott A Biller,  Shinsan M Su,  Stephane de Botton,  Katharine E Yen
Affiliations

Affiliation

  • 1 Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.
PMID: 23558173 DOI: 10.1126/science.1234769
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.

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