Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.
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.
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Fangrui
F
Wu
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Hong
H
Jiang
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Baisong
B
Zheng
Department of Pediatrics-oncology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Mari
M
Kogiso
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Yuan
Y
Yao
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Chao
C
Zhou
Department of Pediatrics-oncology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Xiao-Nan
XN
Li
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
Yongcheng
Y
Song
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005977:Glutarates / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D007700:Kinetics; D008745:Methylation; D008958:Models, Molecular; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013867:Thiohydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005977:Glutarates; D006657:Histones; D013867:Thiohydantoins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase