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

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.