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

• Published in: Chembiochem : a European journal of chemical biology Vol. 19; no. 6; pp. 552 - 561
• Main Authors: Alexandre, Julie Anne Christine, Swan, Michael Kenneth, Latchem, Mike John, Boyall, Dean, Pollard, John Robert, Hughes, Stuart Wynn, Westcott, James
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 16.03.2018; Wiley Subscription Services, Inc
• Subjects: Biochemistry & Molecular Biology; Cancer; Chemistry, Medicinal; Crystal structure; Crystallography, X-Ray; Dioxygenase; Dose-Response Relationship, Drug; Drug development; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Haem; HeLa Cells; Humans; Immune response; Immunosuppressive agents; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inhibitors; Iron; kinetics; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; porphyrins; Science & Technology; Structure-Activity Relationship; Substrates; triazoles; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Tryptophan; Tumors; inhibitors; CATABOLISM; triazoles; enzymes; CRYSTAL-STRUCTURES; porphyrins; 1 IDO1; DISCOVERY; IMIDAZOLEISOINDOLE DERIVATIVES; HEME DIOXYGENASES; REACTION-MECHANISM; cancer; TRYPTOPHAN 2,3-DIOXYGENASE; kinetics; EXPRESSION
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201700560

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. Pocket sized: Indoleamine 2,3‐dioxygenase 1 (IDO1) is an immunosuppressive enzyme employed by cancers to evade the immune system response, and as such is an exciting target for drug discovery. Kinetic, biochemical and structural studies reveal the surprising mechanisms by which a series of IDO1 inhibitors attain potency in cells.