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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Liu Z,Yao Y,Kogiso M,Zheng B,Deng L,Qiu JJ,Dong S,Lv H,Gallo JM,Li XN,Song Y

doi

10.1021/jm500660f

subject

Has Abstract

pub_date

2014-10-23 00:00:00

pages

8307-18

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

57

pub_type

杂志文章

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