Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones.
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.
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine , MS4053, 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
Ann C
AC
Kimble-Hill
Bibek
B
Parajuli
Che-Hong
CH
Chen
Daria
D
Mochly-Rosen
Thomas D
TD
Hurley
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D007211:Indoles; D007527:Isoenzymes; D000444:Aldehyde Dehydrogenase