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
  • 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.

Products