Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5] cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met

Alan B. Northrup*, Matthew H. Katcher, Michael D. Altman, Melissa Chenard, Matthew H. Daniels, Sujal V. Deshmukh, Danielle Falcone, David J. Guerin, Harold Hatch, Chaomin Li, Wei Lu, Bart Lutterbach, Timothy J. Allison, Sangita B. Patel, John F. Reilly, Michael Reutershan, Keith W. Rickert, Craig Rosenstein, Stephen M. Soisson, Alexander A. SzewczakDeborah Walker, Kevin Wilson, Jonathan R. Young, Bo Sheng Pan, Christopher J. Dinsmore

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation.

Original languageEnglish (US)
Pages (from-to)2294-2310
Number of pages17
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
StatePublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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