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.
Ravi Naik  1 ,  Hyun Seung Ban  2  3 ,  Kyusic Jang  1 ,  Inhyub Kim  4  5 ,  Xuezhen Xu  1 ,  Dipesh Harmalkar  1 ,  Seong-Ah Shin  4 ,  Minkyoung Kim  1 ,  Bo-Kyung Kim  4 ,  Jaehyung Park  1 ,  Bonsu Ku  6 ,  Sujin Oh  7 ,  Misun Won  4  5 ,  Kyeong Lee  1
Affiliations
  • 1. College of Pharmacy, Dongguk University , Goyang 10326, Korea.
  • 2. Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Korea.
  • 3. Biomolecular Science, University of Science and Technology , Daejeon 34113, Korea.
  • 4. Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Korea.
  • 5. Functional Genomics, University of Science and Technology , Daejeon 34113, Korea.
  • 6. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology , Daejeon 34141, Korea.
  • 7. New Drug Development Center, Asan Medical Center , Seoul 05505, Korea.
PMID: 28991459 DOI: 10.1021/acs.jmedchem.7b01231
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.

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