Display options
Cite
Pei Z, Mendonca R, Gazzard L, et al. Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2). ACS Med Chem Lett. 2018;9(5):417-421doi: 10.1021/acsmedchemlett.7b00427.
Pei, Z., Mendonca, R., Gazzard, L., Pastor, R., Goon, L., Gustafson, A., VanderPorten, E., Hatzivassiliou, G., Dement, K., Cass, R., Yuen, P. W., Zhang, Y., Wu, G., Lin, X., Liu, Y., & Sellers, B. D. (2018). Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2). ACS medicinal chemistry letters, 9(5), 417-421. https://doi.org/10.1021/acsmedchemlett.7b00427
Pei, Zhonghua, et al. "Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2)." ACS medicinal chemistry letters vol. 9,5 (2018): 417-421. doi: https://doi.org/10.1021/acsmedchemlett.7b00427
Pei Z, Mendonca R, Gazzard L, Pastor R, Goon L, Gustafson A, VanderPorten E, Hatzivassiliou G, Dement K, Cass R, Yuen PW, Zhang Y, Wu G, Lin X, Liu Y, Sellers BD. Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2). ACS Med Chem Lett. 2018 Apr 02;9(5):417-421. doi: 10.1021/acsmedchemlett.7b00427. eCollection 2018 May 10. PMID: 29795752; PMCID: PMC5949840.
Copy Download .nbib Format: NLM
Share it on

ACS Med Chem Lett. 2018 Apr 02;9(5):417-421. doi: 10.1021/acsmedchemlett.7b00427. eCollection 2018 May 10.

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

ACS medicinal chemistry letters

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

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 PMCID: PMC5949840 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

Conflict of interest statement

The authors declare no competing financial interest.

References

  1. Mol Cancer Ther. 2010 Feb;9(2):489-98 - PubMed
  2. Immunity. 2005 May;22(5):633-42 - PubMed
  3. Nature. 2011 Oct 05;478(7368):197-203 - PubMed
  4. Nature. 2014 Jul 10;511(7508):184-90 - PubMed
  5. Drug Metab Dispos. 2003 Oct;31(10):1240-50 - PubMed
  6. Mol Pharmacol. 2016 Nov;90(5):674-688 - PubMed
  7. J Exp Med. 2013 Jul 1;210(7):1389-402 - PubMed
  8. Sci Rep. 2016 Oct 20;6:35169 - PubMed
  9. J Med Chem. 2012 Jun 14;55(11):5270-90 - PubMed
  10. Nat Rev Immunol. 2013 Apr;13(4):227-42 - PubMed
  11. J Med Chem. 2015 Dec 24;58(24):9421-37 - PubMed
  12. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):363-5 - PubMed
  13. J Med Chem. 2009 Dec 10;52(23):7364-7 - PubMed
  14. J Immunother Cancer. 2014 Feb 18;2:3 - PubMed
  15. ACS Med Chem Lett. 2014 Aug 21;5(10):1119-23 - PubMed
  16. J Immunol. 2010 Nov 15;185(10):5953-61 - PubMed
  17. Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2497-502 - PubMed
  18. Bioorg Med Chem. 2011 Feb 15;19(4):1550-61 - PubMed
  19. Blood. 2010 Apr 29;115(17):3520-30 - PubMed
  20. Cancer Immunol Res. 2015 Sep;3(9):978-85 - PubMed
  21. Int J Cancer. 2015 Sep 1;137(5):1095-106 - PubMed

Publication Types