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Cell‐Based Identification of New IDO1 Modulator Chemotypes
Author(s) -
Hennes Elisabeth,
Lampe Philipp,
Dötsch Lara,
Bruning Nora,
Pulvermacher LisaMarie,
Sievers Sonja,
Ziegler Slava,
Waldmann Herbert
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202016004
Subject(s) - cofactor , heme , chemistry , biochemistry , enzyme , indoleamine 2,3 dioxygenase , mechanism of action , high throughput screening , computational biology , biology , amino acid , in vitro , tryptophan
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.