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

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 ser...

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Published in:ACS medicinal chemistry letters 2018-05, Vol.9 (5), p.417-421
Main Authors: Pei, Zhonghua, Mendonca, Rohan, Gazzard, Lewis, Pastor, Richard, Goon, Leanne, Gustafson, Amy, VanderPorten, Erica, Hatzivassiliou, Georgia, Dement, Kevin, Cass, Robert, Yuen, Po-wai, Zhang, Yamin, Wu, Guosheng, Lin, Xingyu, Liu, Yichin, Sellers, Benjamin D
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Language:English
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00427