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

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

  • ACS Med Chem Lett. 2018 Apr 2;9(5):417-421. doi: 10.1021/acsmedchemlett.7b00427.
Zhonghua Pei 1,  Rohan Mendonca 1,  Lewis Gazzard 1,  Richard Pastor 1,  Leanne Goon 1,  Amy Gustafson 1,  Erica VanderPorten 1,  Georgia Hatzivassiliou 1,  Kevin Dement 1,  Robert Cass 1,  Po-Wai Yuen 2,  Yamin Zhang 2,  Guosheng Wu 2,  Xingyu Lin 2,  Yichin Liu 1,  Benjamin D Sellers 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Department of Biochemical and Cellular Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Pharmaron-Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
PMID: 29795752 DOI: 10.1021/acsmedchemlett.7b00427
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.

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