O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1.

ABSTRACT: Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivative

SUBMITTER: Malachowski WP 

PROVIDER: S-EPMC4724314 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature