Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2)

Zhonghua Pei, Rohan Mendonca, Lewis Gazzard, Richard Pastor, Leanne Goon, Amy Gustafson, Erica VanderPorten, Georgia Hatzivassiliou, Kevin Dement, Robert Cass, Po-wai Yuen, Yamin Zhang, Guosheng Wu, Xingyu Lin, Yichin Liu, Benjamin D. Sellers

Index: 10.1021/acsmedchemlett.7b00427

Full Text: HTML

Abstract

Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number of cancers; therefore, TDO inhibition may be a useful therapeutic intervention for cancers. We identified an aminoisoxazole series as potent TDO2 inhibitors from a high-throughput screen (HTS). An extensive medicinal chemistry effort revealed that both the amino group and the isoxazole moiety are important for TDO2 inhibitory activity. Computational modeling yielded a binding hypothesis and provided insight into the observed structure–activity relationships. The optimized compound 21 is a potent TDO2 inhibitor with modest selectivity over indolamine 2,3-dioxygenase 1 (IDO1) and with improved human whole blood stability.