Open AccessImplementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors
Author(s) -
Brendan T. Parr,
Richard Pastor,
Benjamin D. Sellers,
Zhonghua Pei,
Firoz A. Jaipuri,
Georgette Castanedo,
Lewis Gazzard,
Sanjeev Kumar,
Xiaokai Li,
Wen Li,
Rohan Mendonca,
Roheeth Kumar Pavana,
Hima Potturi,
Cheng Shao,
Venkata Velvadapu,
Jesse P. Waldo,
Guosheng Wu,
Powai Yuen,
Zuhui Zhang,
Yamin Zhang,
S.F. Harris,
Angela Oh,
Antonio G. DiPasquale,
Kevin DeMent,
Hank La,
Leanne Goon,
Amy Gustafson,
Erica C. VanderPorten,
Mario R. Mautino,
Yichin Liu
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00004
Subject(s) - chemistry , cytochrome p450 , cyp3a4 , kynurenine , pharmacology , heme , drug , indoleamine 2,3 dioxygenase , therapeutic index , dioxygenase , computational biology , tryptophan , stereochemistry , biochemistry , enzyme , biology , amino acid
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.