ACS Medicinal Chemistry Letters p. 541 - 549 (2020)
Update date:2022-08-05
Topics:
Castanedo, Georgette M.
Dement, Kevin
Dipasquale, Antonio
Gazzard, Lewis
Goon, Leanne
Gustafson, Amy
Harris, Seth F.
Jaipuri, Firoz A.
Kumar, Sanjeev
La, Hank
Li, Xiaokai
Liu, Wen
Liu, Yichin
Mautino, Mario R.
Mendonca, Rohan
Oh, Angela J.
Parr, Brendan T.
Pastor, Richard
Pavana, Roheeth K.
Pei, Zhonghua
Potturi, Hima
Sellers, Benjamin D.
Shao, Cheng
Vanderporten, Erica C.
Velvadapu, Venkata
Waldo, Jesse P.
Wu, Guosheng
Yuen, Po-Wai
Zhang, Yamin
Zhang, Zuhui
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.
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