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

J Med Chem. 2017 Oct 26;60(20):8631-8646. doi: 10.1021/acs.jmedchem.7b01231. Epub 2017 Oct 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Malate Dehydrogenase / antagonists & inhibitors*
  • Mice
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Xenograft Model Antitumor Assays
  • meta-Aminobenzoates / pharmacology*


  • Anilides
  • Enzyme Inhibitors
  • Isoenzymes
  • meta-Aminobenzoates
  • methyl 3-(3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propanamido)benzoate
  • Malate Dehydrogenase