• Fang Wang, 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, and Katharine E Yen.
• Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.
• Science. 2013 May 3;340(6132):622-6.

AbstractA 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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