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
| Autor: | Michael K. Swan, Mike John Latchem, Dean Boyall, Stuart W. Hughes, Julie Anne Christine Alexandre, John Pollard, James Westcott |
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| Rok vydání: | 2018 |
| Předmět: |
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Molecular 0301 basic medicine Crystallography X-Ray 010402 general chemistry 01 natural sciences Biochemistry Cofactor Structure-Activity Relationship 03 medical and health sciences Oxidoreductase medicine Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Enzyme Inhibitors Indoleamine 2 3-dioxygenase Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Tryptophan Substrate (chemistry) Triazoles Ligand (biochemistry) 0104 chemical sciences 030104 developmental biology Enzyme chemistry Mechanism of action biology.protein Molecular Medicine medicine.symptom HeLa Cells |
| Zdroj: | ChemBioChem. 19:552-561 |
| ISSN: | 1439-4227 |
| DOI: | 10.1002/cbic.201700560 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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