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Title 

Methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)-propanamido)benzoate as a novel and dual malate dehydrogenase (MDH) 1/2 inhibitor targeting cancer metabolism

Authors 

R NaikHyun Seung BanK JangI KimX XuD HarmalkarS A ShinM KimB K KimJ ParkBonsu KuMi Sun WonK Lee

Publisher 

American Chemical Society

Issue Date 

2017

Citation 

Journal of Medicinal Chemistry

Abstract 

Previously, we reported a hypoxia-inducible factor (HIF)-1 inhibitor LW6 containing an (aryloxyacetylamino)benzoic acid moiety inhibits malate dehydrogenase 2 (MDH2) using a chemical biology approach. Structure-activity relationship studies on a series of (aryloxyacetylamino)benzoic acids identified selective MDH1, MDH2, and dual inhibitors, which were used to study the relationship between MDH enzyme activity and HIF-1 inhibition. We hypothesized that dual inhibition of MDH1 and MDH2 might be a powerful approach to target cancer metabolism and selected methyl-3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)-benzoate (16c) as the most potent dual inhibitor. Kinetic studies revealed that compound 16c competitively inhibited MDH1 and MDH2. Compound 16c inhibited mitochondrial respiration and hypoxia-induced HIF-1α accumulation. In xenograft assays using HCT116 cells, compound 16c demonstrated significant in vivo antitumor efficacy. This finding provides concrete evidence that inhibition of both MDH1 and MDH2 may provide a valuable platform for developing novel therapeutics that target cancer metabolism and tumor growth

ISSN 

0022-2623

Link 

http://dx.doi.org/10.1021/acs.jmedchem.7b01231

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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