title: A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.
abstract: OBJECTIVE
  The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase.
  
  
  METHODS
  Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments.
  
  
  RESULTS
  INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers.
  
  
  CONCLUSIONS
  Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.
authors.affiliation: Incyte Corporation, Wilmington, Delaware 19880, USA. xliu@incyte.com
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Gengjie
authors.initials: G
authors.lastname: Yang
authors.forename: Cindy
authors.initials: C
authors.lastname: Marando
authors.forename: Holly K
authors.initials: HK
authors.lastname: Koblish
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Hall
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Elham
authors.initials: E
authors.lastname: Behshad
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Jason
authors.initials: J
authors.lastname: Boer
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Chunhong
authors.initials: C
authors.lastname: He
authors.forename: Meizhong
authors.initials: M
authors.lastname: Xu
authors.forename: Jincong
authors.initials: J
authors.lastname: Zhuo
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D020239:Receptor Cross-Talk / Q000187:drug effects*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014227:Triazines; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D014227:Triazines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; C000613976:capmatinib