Inhibition of cancer-associated mutant isocitrate dehydrogenases: Synthesis, structure-activity relationship, and selective antitumor activity

Zhen Liu, Yuan Yao, Mari Kogiso, Baisong Zheng, Lisheng Deng, Jihui J. Qiu, Shuo Dong, Hua Lv, James M. Gallo, Xiao Nan Li, Yongcheng Song*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

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 R2 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.

Original languageEnglish (US)
Pages (from-to)8307-8318
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number20
DOIs
StatePublished - Oct 23 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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