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New 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
Author(s) -
Alexandre Julie Anne Christine,
Swan Michael Kenneth,
Latchem Mike John,
Boyall Dean,
Pollard John Robert,
Hughes Stuart Wynn,
Westcott James
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700560
Subject(s) - indoleamine 2,3 dioxygenase , tryptophan , enzyme , chemistry , cofactor , ligand (biochemistry) , stereochemistry , mechanism of action , biochemistry , triazole , binding site , amino acid , in vitro , receptor , organic chemistry
Indoleamine‐2,3 dioxygenase 1 (IDO1) 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, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4‐amino‐1,2,3‐triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co‐complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed 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 partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1‐targeted drugs.