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Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):3249-3254. doi: 10.1073/pnas.1719190115. Epub 2018 Mar 12.

Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.

Author information

1
Department of Chemistry, Princeton University, Princeton, NJ 08544.
2
Immuno-oncology Biology, Bristol-Myers Squibb Co., Princeton, NJ 08543.
3
Molecular Discovery Technologies, Bristol-Myers Squibb Co., Princeton, NJ 08543.
4
Department of Discovery Chemistry, Bristol-Myers Squibb Co., Princeton, NJ 08543.
5
Leads Discovery and Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543.
6
Department of Radiochemistry, Bristol-Myers Squibb Co., Princeton, NJ 08543.
7
Department of Chemistry, Princeton University, Princeton, NJ 08544; jtgroves@princeton.edu.

Abstract

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

KEYWORDS:

IDO1; cancer; heme; kynurenine

PMID:
29531094
PMCID:
PMC5879690
DOI:
10.1073/pnas.1719190115
[Indexed for MEDLINE]
Free PMC Article

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