Design, synthesis, and biological evaluation of potent c-Met inhibitors

Noel D. D'Angelo, Steven F. Bellon, Shon K. Booker, Yuan Cheng, Angela Coxon, Celia Dominguez, Ingrid Fellows, Douglas Hoffman, Randall Hungate, Paula Kaplan-Lefko, Matthew R. Lee, Chun Li, Longbin Liu, Elizabeth Rainbeau, Paul J. Reider, Karen Rex, Aaron Siegmund, Yaxiong Sun, Andrew S. Tasker, Ning XiShimin Xu, Yajing Yang, Yihong Zhang, Teresa L. Burgess, Isabelle Dussault, Tae Seong Kim

Research output: Contribution to journalArticle

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Abstract

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)5766-5779
Number of pages14
JournalJournal of Medicinal Chemistry
Volume51
Issue number18
DOIs
StatePublished - Sep 25 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    D'Angelo, N. D., Bellon, S. F., Booker, S. K., Cheng, Y., Coxon, A., Dominguez, C., Fellows, I., Hoffman, D., Hungate, R., Kaplan-Lefko, P., Lee, M. R., Li, C., Liu, L., Rainbeau, E., Reider, P. J., Rex, K., Siegmund, A., Sun, Y., Tasker, A. S., ... Kim, T. S. (2008). Design, synthesis, and biological evaluation of potent c-Met inhibitors. Journal of Medicinal Chemistry, 51(18), 5766-5779. https://doi.org/10.1021/jm8006189