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

Cited 20 time in scopus
Metadata Downloads
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
Author(s)
R Naik; Hyun Seung Ban; K Jang; I Kim; X Xu; D Harmalkar; S A Shin; M Kim; Bo Kyung Kim; J Park; Bonsu KuMi Sun Won; K Lee
Bibliographic Citation
Journal of Medicinal Chemistry, vol. 60, no. 20, pp. 8631-8646
Publication Year
2017
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
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/acs.jmedchem.7b01231
Type
Article
Appears in Collections:
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Files in This Item:
  • There are no files associated with this item.


Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.