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
  • 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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