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

作者：Naik Ravi; Ban Hyun Seung; Jang Kyusic; Kim Inhyub; Xu Xuezhen; Harmalkar Dipesh; Shin Seong Ah; Kim Minkyoung; Kim Bo Kyung; Park Jaehyung; Ku Bonsu; On Sujin; Won Misun^*; Lee Kyeong^*

来源：Journal of Medicinal Chemistry, 2017, 60(20): 8631-8646.

DOI：10.1021/acs.jmedchem.7b01231

Previously, we reported a hypoxia-inducible factor (HIF)-l 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-1 alpha 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.

• 出版日期2017-10-26