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Novel 4-amino-1,2,3-triazole inhibitors of indoleamine 2,3-dioxygenase form a long-lived complex with the enzyme and display exquisite cellular potency

DOI: 10.1002/cbic.201700560 DOI Help

Authors: Julie Alexandre (Vertex Pharmaceuticals Europe Ltd) , Michael Swan (Vertex Pharmaceuticals Europe Ltd) , Mike Latchem (Vertex Pharmaceuticals Europe Ltd) , Dean Boyall (Vertex Pharmaceuticals Europe Ltd) , John Pollard (Vertex Pharmaceuticals Europe Ltd) , Stuart Hughes (Vertex Pharmaceuticals Europe Ltd) , James Westcott (Vertex Pharmaceuticals Europe Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chembiochem

State: Published (Approved)
Published: December 2017
Diamond Proposal Number(s): 5800

Abstract: Indoleamine-2,3 dioxygenase (IDO) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO has become an attractive target for cancer treatment. We have identified a novel series of highly cell potent IDO inhibitors based on a 4-amino-1,2,3-triazole core. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a non-competitive kinetic mechanism-of-action with respect to the tryptophan substrate. Surprisingly, they bind in the tryptophan pocket, making a direct ligand interaction with the haem iron of the porphyrin cofactor. We propose that these data can be rationalised by an ordered binding mechanism in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which we propose partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO targeted drugs.

Journal Keywords: Slow-binding kinetics; X-ray crystal structure; UV-visible spectroscopy; haem-porphyrin; mode-of-inhibition

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I03-Macromolecular Crystallography

Added On: 08/01/2018 11:10

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)