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3. Design, Synthesis, and Biological Evaluation of Potent c-Met Inhibitors

Author

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

Published
2008
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10. Design, synthesis, and biological evaluation of potent c-Met inhibitors.

Author

D'Angelo ND, Bellon SF, Booker SK, Cheng Y, Coxon A, Dominguez C, Fellows I, Hoffman D, Hungate R, Kaplan-Lefko P, Lee MR, Li C, Liu L, Rainbeau E, Reider PJ, Rex K, Siegmund A, Sun Y, Tasker AS, Xi N, Xu S, Yang Y, Zhang Y, Burgess TL, Dussault I, and Kim TS

Subjects
Cell Line, Tumor, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors
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.

Published
2008
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