Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

• Published in: Science (American Association for the Advancement of Science) Vol. 340; no. 6132; pp. 622 - 626
• Main Authors: Wang, Fang, Travins, Jeremy, DeLaBarre, Byron, Penard-Lacronique, Virginie, Schalm, Stefanie, Hansen, Erica, Straley, Kimberly, Kernytsky, Andrew, Liu, Wei, Gliser, Camelia, Yang, Hua, Gross, Stefan, Artin, Erin, Saada, Veronique, Mylonas, Elena, Quivoron, Cyril, Popovici-Muller, Janeta, Saunders, Jeffrey O., Salituro, Francesco G., Yan, Shunqi, Murray, Stuart, Wei, Wentao, Gao, Yi, Dang, Lenny, Dorsch, Marion, Agresta, Sam, Schenkein, David P., Biller, Scott A., Su, Shinsan M., de Botton, Stephane, Yen, Katharine E.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 03.05.2013; The American Association for the Advancement of Science; AAAS
• Subjects: Allosteric Site; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Blasts; Bone marrow cells; Cancer; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Cells; Cells, Cultured; Cellular biology; Cellular differentiation; Crystallography, X-Ray; Dehydrogenases; Drug therapy; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Erythropoiesis - drug effects; Gene Expression Regulation, Leukemic; Glutarates - metabolism; Hematopoiesis - drug effects; Hematopoietic stem cells; Humans; Individualized Instruction; Inhibition; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - chemistry; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Mesenchymal stem cells; Molecular Targeted Therapy; Molecules; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutation; Myeloid leukemia; Phenylurea Compounds - chemistry; Phenylurea Compounds - metabolism; Phenylurea Compounds - pharmacology; Point Mutation; Protein Multimerization; Protein Structure, Secondary; Small Molecule Libraries; Stem cells; Sulfonamides - chemistry; Sulfonamides - metabolism; Sulfonamides - pharmacology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1234769

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.