4IWD

Structure of dually phosphorylated c-MET receptor kinase in complex with an MK-8033 analog

Summary for 4IWD

• Entry DOI: 10.2210/pdb4iwd/pdb
• Related: 3r7o
• Descriptor: Hepatocyte growth factor receptor, 1-{5-oxo-3-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}-N-(pyridin-2-ylmethyl)methanesulfonamide (3 entities in total)
• Functional Keywords: protein kinase, tyrosine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 35550.94

Authors

Soisson, S.M.,Northrup, A.,Rickert, K.,Patel, S.,Allison, T. (deposition date: 2013-01-23, release date: 2013-12-11, Last modification date: 2017-11-15)

Primary citation

Northrup, A.B.,Katcher, M.H.,Altman, M.D.,Chenard, M.,Daniels, M.H.,Deshmukh, S.V.,Falcone, D.,Guerin, D.J.,Hatch, H.,Li, C.,Lu, W.,Lutterbach, B.,Allison, T.J.,Patel, S.B.,Reilly, J.F.,Reutershan, M.,Rickert, K.W.,Rosenstein, C.,Soisson, S.M.,Szewczak, A.A.,Walker, D.,Wilson, K.,Young, J.R.,Pan, B.S.,Dinsmore, C.J.
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., 56:2294-2310, 2013

PubMed 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.

PubMed: 23379595
DOI: 10.1021/jm301619u

Experimental method

X-RAY DIFFRACTION (1.99 Å)