Computer-aided discovery and biological characterization of human lactate dehydrogenase 5 inhibitors with anti-osteosarcoma activity

Bioorg Med Chem Lett. 2018 Jul 15;28(13):2229-2233. doi: 10.1016/j.bmcl.2018.05.052. Epub 2018 May 28.

Abstract

Human lactate dehydrogenase 5 (hLDH5) is overexpressed in various tissues of human tumors, which could be a potential therapeutic target for cancer treatment. Herein, we describe the computer-aided discovery and biological characterizations of hLDH5 inhibitors with anti-osteosarcoma activity. Biochemical assay indicated that the identified compounds 3 and 9 strongly inhibited hLDH5 function with EC50 values of 0.67 and 0.39 µM, respectively. The MTT assay revealed that most of the identified inhibitors had little effect on MG-63 cell proliferation at 4 µM, only 9 reduced the cancer cell proliferation at the same concentration, with an IC50 value of 3.18 µM. Our data suggested that 9 could be a starting lead of developing potent hLDH5 inhibitor for the anti-osteosarcoma agents in cancer treatment.

Keywords: Anticancer drug; Cancer metabolism; Metabolic reprogramming; Proliferation; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays / methods
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / chemistry
  • Lactate Dehydrogenase 5
  • Lactic Acid / metabolism
  • Molecular Docking Simulation
  • Osteosarcoma / drug therapy*

Substances

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