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 Hurley

Research output: Contribution to journalArticle

18 Citations (Scopus)

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

Fingerprint

Aldehyde Dehydrogenase
Isoenzymes
X Ray Crystallography
Structure-Activity Relationship
Metabolic Networks and Pathways
Aldehydes
Cysteine
Catalytic Domain
indole

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones. / Kimble-Hill, Ann C.; Parajuli, Bibek; Chen, Che Hong; Mochly-Rosen, Daria; Hurley, Thomas.

In: Journal of Medicinal Chemistry, Vol. 57, No. 3, 13.02.2014, p. 714-722.

Research output: Contribution to journalArticle

Kimble-Hill, Ann C. ; Parajuli, Bibek ; Chen, Che Hong ; Mochly-Rosen, Daria ; Hurley, Thomas. / Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 3. pp. 714-722.
@article{d0e961690bc94b94b78f16b41f6a3b91,
title = "Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones",
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.",
author = "Kimble-Hill, {Ann C.} and Bibek Parajuli and Chen, {Che Hong} and Daria Mochly-Rosen and Thomas Hurley",
year = "2014",
month = "2",
day = "13",
doi = "10.1021/jm401377v",
language = "English",
volume = "57",
pages = "714--722",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Development of selective inhibitors for aldehyde dehydrogenases based on substituted indole-2,3-diones

AU - Kimble-Hill, Ann C.

AU - Parajuli, Bibek

AU - Chen, Che Hong

AU - Mochly-Rosen, Daria

AU - Hurley, Thomas

PY - 2014/2/13

Y1 - 2014/2/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84894076119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894076119&partnerID=8YFLogxK

U2 - 10.1021/jm401377v

DO - 10.1021/jm401377v

M3 - Article

VL - 57

SP - 714

EP - 722

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -