Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer.

Abstract

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

DOI: 10.1021/jm200112k

Cite this paper

@article{Katz2011DiscoveryOA, title={Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer.}, author={Jason D Katz and James P Jewell and David J Guerin and Jongwon Lim and Christopher J Dinsmore and Sujal V. Deshmukh and Bo-Sheng Pan and Christopher G Marshall and Wei Lu and Michael D. Altman and William K. Dahlberg and Lenora J Davis and Danielle Falcone and Ana E Gabarda and Gaozhen Hang and Harold Hatch and Rachael Holmes and Kaiko Kunii and Kevin J Lumb and Bart A Lutterbach and Robert J Mathvink and Naim Nazef and Sangita B Patel and Xianlu Qu and John F. Reilly and Keith W Rickert and Craig Rosenstein and Stephen M. Soisson and Kerrie B Spencer and Alexander A. Szewczak and Deborah Walker and Wenxian Wang and Jonathan Young and Qinwen Zeng}, journal={Journal of medicinal chemistry}, year={2011}, volume={54 12}, pages={4092-108} }