Structure-based optimization of hydroxylactam as potent, cell-active inhibitors of lactate dehydrogenase

Bioorg Med Chem Lett. 2022 Mar 1:59:128576. doi: 10.1016/j.bmcl.2022.128576. Epub 2022 Jan 19.

Abstract

Structure-based design was utilized to optimize 6,6-diaryl substituted dihydropyrone and hydroxylactam to obtain inhibitors of lactate dehydrogenase (LDH) with low nanomolar biochemical and single-digit micromolar cellular potencies. Surprisingly the replacement of a phenyl with a pyridyl moiety in the chemical structure revealed a new binding mode for the inhibitors with subtle conformational change of the LDHA active site. This led to the identification of a potent, cell-active hydroxylactam inhibitor exhibiting an in vivo pharmacokinetic profile suitable for mouse tumor xenograft study.

Keywords: Glycolysis; Lactate dehydrogenase; Structure-based design; Tumor metabolism; X-ray crystal structure.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • L-Lactate Dehydrogenase / antagonists & inhibitors*
  • L-Lactate Dehydrogenase / metabolism
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Lactams
  • L-Lactate Dehydrogenase