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J Med Chem. 2015 Sep 10;58(17):6899-6908. doi: 10.1021/acs.jmedchem.5b00684. Epub 2015 Aug 26.

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

Author information

1
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2
Department of Pediatrics-oncology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
#
Contributed equally

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.

PMID:
26280302
PMCID:
PMC4567406
DOI:
10.1021/acs.jmedchem.5b00684
[Indexed for MEDLINE]
Free PMC Article

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