Cell-Based Identification of New IDO1 Modulator Chemotypes.
cancer
fluorescence
heme proteins
high throughput screening
immunology
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
26 04 2021
26 04 2021
Historique:
revised:
08
01
2021
received:
01
12
2020
pubmed:
11
2
2021
medline:
7
8
2021
entrez:
10
2
2021
Statut:
ppublish
Résumé
The immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO1) strengthens cancer immune escape, and inhibition of IDO1 by means of new chemotypes and mechanisms of action is considered a promising opportunity for IDO1 inhibitor discovery. IDO1 is a cofactor-binding, redox-sensitive protein, which calls for monitoring of IDO1 activity in its native cellular environment. We developed a new, robust fluorescence-based assay amenable to high throughput, which detects kynurenine in cells. Screening of a ca. 150 000-member compound library discovered unprecedented, potent IDO1 modulators with different mechanisms of action, including direct IDO1 inhibitors, regulators of IDO1 expression, and inhibitors of heme synthesis. Three IDO1-modulator chemotypes were identified that bind to apo-IDO1 and compete with the heme cofactor. Our new cell-based technology opens up novel opportunities for medicinal chemistry programs in immuno-oncology.
Identifiants
pubmed: 33565680
doi: 10.1002/anie.202016004
pmc: PMC8252559
doi:
Substances chimiques
Coumarins
0
Enzyme Inhibitors
0
Fluorescent Dyes
0
IDO1 protein, human
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Kynurenine
343-65-7
coumarin
A4VZ22K1WT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9869-9874Informations de copyright
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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