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

Ann C. Kimble-Hill, Bibek Parajuli, Che Hong Chen, Daria Mochly-Rosen, Thomas D. Hurley

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)714-722
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
StatePublished - Feb 13 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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