title: 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.
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.
authors: Department of Chemistry, Merck & Co., Inc. , 33 Avenue Louis Pasteur, BMB-3, Boston, Massachusetts 02115, USA. alan_northrup@merck.com
authors: Alan B
authors: AB
authors: Northrup
authors: Matthew H
authors: MH
authors: Katcher
authors: Michael D
authors: MD
authors: Altman
authors: Melissa
authors: M
authors: Chenard
authors: Matthew H
authors: MH
authors: Daniels
authors: Sujal V
authors: SV
authors: Deshmukh
authors: Danielle
authors: D
authors: Falcone
authors: David J
authors: DJ
authors: Guerin
authors: Harold
authors: H
authors: Hatch
authors: Chaomin
authors: C
authors: Li
authors: Wei
authors: W
authors: Lu
authors: Bart
authors: B
authors: Lutterbach
authors: Timothy J
authors: TJ
authors: Allison
authors: Sangita B
authors: SB
authors: Patel
authors: John F
authors: JF
authors: Reilly
authors: Michael
authors: M
authors: Reutershan
authors: Keith W
authors: KW
authors: Rickert
authors: Craig
authors: C
authors: Rosenstein
authors: Stephen M
authors: SM
authors: Soisson
authors: Alexander A
authors: AA
authors: Szewczak
authors: Deborah
authors: D
authors: Walker
authors: Kevin
authors: K
authors: Wilson
authors: Jonathan R
authors: JR
authors: Young
authors: Bo-Sheng
authors: BS
authors: Pan
authors: Christopher J
authors: CJ
authors: Dinsmore
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004285:Dogs; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001567:Benzocycloheptenes; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C581209:1-(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; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases