Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.

Abstract	Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce α-ketoglutaric acid (α-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many α-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.
Authors	Fangrui Wu, Hong Jiang, Baisong Zheng, Mari Kogiso, Yuan Yao, Chao Zhou, Xiao-Nan Li, Yongcheng Song
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 17 Pg. 6899-6908 (Sep 10 2015) ISSN: 1520-4804 [Electronic] United States
PMID	26280302 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Glutarates Histones Thiohydantoins alpha-hydroxyglutarate Isocitrate Dehydrogenase
Topics	Antineoplastic Agents (chemical synthesis, chemistry, pharmacology) Cell Line, Tumor Cell Proliferation (drug effects) Crystallography, X-Ray Drug Screening Assays, Antitumor Glutarates (metabolism) Histones (metabolism) Humans Isocitrate Dehydrogenase (antagonists & inhibitors, chemistry, genetics) Kinetics Methylation Models, Molecular Mutation Neoplastic Stem Cells (drug effects, pathology) Protein Binding Protein Conformation Structure-Activity Relationship Thermodynamics Thiohydantoins (chemical synthesis, chemistry, pharmacology)

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