Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors
| Autor: | Wen Liu, Amy Gustafson, Firoz Jaipuri, Erica VanderPorten, Leanne Goon, Yamin Zhang, Guosheng Wu, Zuhui Zhang, Antonio G. DiPasquale, Xiaokai Li, Angela J. Oh, Lewis J. Gazzard, Seth F. Harris, Jesse Waldo, Roheeth Kumar Pavana, Yichin Liu, Venkata Velvadapu, Cheng Shao, Yuen Po-Wai, Mario R. Mautino, Zhonghua Pei, Hank La, Hima Potturi, Georgette Castanedo, Benjamin D. Sellers, Kevin DeMent, Sanjeev Kumar, Richard Pastor, Rohan Mendonca, Brendan T. Parr |
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| Rok vydání: | 2020 |
| Předmět: |
Kynurenine pathway
biology CYP3A4 010405 organic chemistry Organic Chemistry Cytochrome P450 Oxidoreductase inhibitor 01 natural sciences Biochemistry Small molecule 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry In vivo Drug Discovery biology.protein Indoleamine 2 3-dioxygenase Heme |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.0c00004 |
| Popis: | [Image: see text] A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug–drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme. |
| Databáze: | OpenAIRE |
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