학술논문
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.
Document Type
Article
Author
Katz, Jason D.; Jewell, James P.; Guerin, David J.; Lim, Jongwon; Dinsmore, Christopher J.; Deshmukh, Sujal V.; Pan, Bo-Sheng; Marshall, C. Gary; Lu, Wei; Altman, Michael D.; Dahlberg, William K.; Davis, Lenora; Falcone, Danielle; Gabarda, Ana E.; Hang, Gaozhen; Hatch, Harold; Holmes, Rachael; Kunii, Kaiko; Lumb, Kevin J.; Lutterbach, Bart
Source
Subject
*PYRIDINE
*CANCER treatment
*PROTEIN-tyrosine kinases
*ENZYME inhibitors
*MEMBRANE proteins
*CELLULAR signal transduction
*PHENOTYPES
*ANTINEOPLASTIC agents
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Language
ISSN
0022-2623
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 81and provides a description of its unique biochemical properties. [ABSTRACT FROM AUTHOR]