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Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors

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posted on 06.03.2020, 18:10 by Brendan T. Parr, Richard Pastor, Benjamin D. Sellers, Zhonghua Pei, Firoz A. Jaipuri, Georgette M. Castanedo, Lewis Gazzard, Sanjeev Kumar, Xiaokai Li, Wen Liu, Rohan Mendonca, Roheeth K. Pavana, Hima Potturi, Cheng Shao, Venkata Velvadapu, Jesse P. Waldo, Guosheng Wu, Po-wai Yuen, Zuhui Zhang, Yamin Zhang, Seth F. Harris, Angela J. Oh, Antonio DiPasquale, Kevin Dement, Hank La, Leanne Goon, Amy Gustafson, Erica C. VanderPorten, Mario R. Mautino, Yichin Liu
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.