Discovery of human lactate dehydrogenase 5 inhibitors (hLDH5) with anti-lung cancer activity through an in silico method and biological validation

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2459-2463. doi: 10.1016/j.bmcl.2019.07.029. Epub 2019 Jul 19.

Abstract

Human lactate dehydrogenase 5 (hLDH5) is an important metabolic enzyme playing critical roles in the anaerobic glycolysis. Herein, we employed an in silico method and biological validation to identify a novel hLDH5 inhibitor with a promising cellular activity under hypoxia condition. The identified compound 9 bound to hLDH5 with a Kd value of 1.02 µM, and inhibited the enzyme with an EC50 value of 0.7 µM. Compound 9 exhibited a weak potency against NCI-H1975 cell proliferation under normal condition (IC50 = 36.5 µM), while dramatically increased to 5.7 µM under hypoxia condition. In line with the observation, hLDH5 expression in NCI-H1975 cell under hypoxia condition is much higher as compared to the normal oxygenated condition, indicating the hLDH5 inhibition may contribute to the cancer cell death.

Keywords: Anticancer; Biochemical activity; Cancer metabolism; Human lactate dehydrogenase 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Catalytic Domain
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Lactate Dehydrogenase 5 / antagonists & inhibitors*
  • Lactate Dehydrogenase 5 / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Molecular Conformation
  • Molecular Docking Simulation
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Lactate Dehydrogenase 5