Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line

Bioorg Med Chem Lett. 2016 Jan 1;26(1):72-5. doi: 10.1016/j.bmcl.2015.11.025. Epub 2015 Nov 10.

Abstract

Targeting LDHA represents a promising strategy for the development of new anti-cancer agents. We report herein the identification of a potent compound as a direct LDHA inhibitor. The in vitro enzymatic assay revealed that the VS-2 had good inhibitory potency (IC50=0.25μM) to LDHA. Cytotoxic assay suggested that the VS-2 could inhibit MCF-7 cancer cell growth, with the IC50 value low to 1.54μM. The seahorse XF24 experiment validated that the VS-2 served as a modulator to reprogram MCF-7 cancer cell metabolism from glycolysis to mitochondrial respiration.

Keywords: Cytotoxic assay; Enzymatic assay; Lactate dehydrogenase A; Virtual screening.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glycolysis / drug effects
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / metabolism
  • Lactate Dehydrogenase 5
  • MCF-7 Cells
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Isoenzymes
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5