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Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

2013; American Association for the Advancement of Science; Volume: 340; Issue: 6132 Linguagem: Inglês

10.1126/science.1234769

1095-9203

Fang Wang, Jeremy Travins, Byron DeLaBarre, Virginie Penard‐Lacronique, Stefanie Schalm, Erica Hansen, Kimberly Straley, Andrew Kernytsky, Wei Liu, Camelia Gliser, Hua Yang, Stefan Größ, Erin Artin, Véronique Saada, Elena Mylonas, Cyril Quivoron, Janeta Popovici-Müller, 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, Stéphane de Botton, Katharine Yen,

Cancer, Hypoxia, and Metabolism

IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis ). F. Wang et al. (p. 622 , published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626 , published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation.