Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones

J Med Chem. 2014 Feb 13;57(3):714-22. doi: 10.1021/jm401377v. Epub 2014 Jan 31.

Abstract

Aldehyde dehydrogenases (ALDH) participate in multiple metabolic pathways and have been indicated to play a role in several cancerous disease states. Our laboratory is interested in developing novel and selective ALDH inhibitors. We looked to further work recently published by developing a class of isoenzyme-selective inhibitors using similar indole-2,3-diones that exhibit differential inhibition of ALDH1A1, ALDH2, and ALDH3A1. Kinetic and X-ray crystallography data suggest that these inhibitors are competitive against aldehyde binding, forming direct interactions with active-site cysteine residues. The selectivity is precise in that these compounds appear to interact directly with the catalytic nucleophile, Cys243, in ALDH3A1 but not in ALDH2. In ALDH2, the 3-keto group is surrounded by the adjacent Cys301/303. Surprisingly, the orientation of the interaction changes depending on the nature of the substitutions on the basic indole ring structure and correlates well with the observed structure-activity relationships for each ALDH isoenzyme.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Dehydrogenase / antagonists & inhibitors*
  • Aldehyde Dehydrogenase / chemistry
  • Crystallography, X-Ray
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Kinetics
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Indoles
  • Isoenzymes
  • Aldehyde Dehydrogenase

Associated data

  • PDB/4KWF
  • PDB/4KWG
  • PDB/4L10