2. Academic Validation
  3. 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

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

  • J Med Chem. 2013 Mar 28;56(6):2294-310. doi: 10.1021/jm301619u.
Alan B Northrup 1,  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 Szewczak,  Deborah Walker,  Kevin Wilson,  Jonathan R Young,  Bo-Sheng Pan,  Christopher J Dinsmore
Affiliations

Affiliation

  • 1 Department of Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, BMB-3, Boston, Massachusetts 02115, USA. alan_northrup@merck.com
PMID: 23379595 DOI: 10.1021/jm301619u
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.

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