| Literature DB >> 32292562 |
Brendan T Parr1, Richard Pastor1, Benjamin D Sellers1, Zhonghua Pei1, Firoz A Jaipuri2, Georgette M Castanedo1, Lewis Gazzard1, Sanjeev Kumar2, Xiaokai Li2, Wen Liu1, Rohan Mendonca1, Roheeth K Pavana2, Hima Potturi2, Cheng Shao3, Venkata Velvadapu2, Jesse P Waldo2, Guosheng Wu3, Po-Wai Yuen3, Zuhui Zhang2, Yamin Zhang3, Seth F Harris1, Angela J Oh1, Antonio DiPasquale1, Kevin Dement1, Hank La1, Leanne Goon1, Amy Gustafson1, Erica C VanderPorten1, Mario R Mautino2, Yichin Liu1.
Abstract
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.Entities:
Year: 2020 PMID： 32292562 PMCID： PMC7153281 DOI： 10.1021/acsmedchemlett.0c00004
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345