title: Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity.
abstract: Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of α-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure-activity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with Ki values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R(2) of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood-brain barrier in a cell-based model assay and exhibit potent and selective activity (EC50 = 0.26-1.8 μM) against glioma cells with the IDH1 R132H mutation.
authors.affiliation: Department of Pharmacology, ⊥Department of Pediatrics-oncology, ∥Department of Medicine, and ‡Dan L. Duncan Cancer Center, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Mari
authors.initials: M
authors.lastname: Kogiso
authors.forename: Baisong
authors.initials: B
authors.lastname: Zheng
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Jihui J
authors.initials: JJ
authors.lastname: Qiu
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Hua
authors.initials: H
authors.lastname: Lv
authors.forename: James M
authors.initials: JM
authors.lastname: Gallo
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy / Q000473:pathology; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051379:Mice; D011728:Pyridones / Q000737:chemistry; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005977:Glutarates; D011728:Pyridones; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human