title: Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families.
abstract: OBJECTIVE
  The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514.
  
  
  METHODS
  The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI.
  
  
  RESULTS
  BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy.
  
  
  CONCLUSIONS
  By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.
authors.affiliation: Oncology Discovery, Discovery Chemistry, and Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research, Princeton, NJ 08543, USA. tai.wong@bms.com
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Craig
authors.initials: C
authors.lastname: Fairchild
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Brian
authors.initials: B
authors.lastname: Fink
authors.forename: Ashvinikumar
authors.initials: A
authors.lastname: Gavai
authors.forename: Amy
authors.initials: A
authors.lastname: Hammell
authors.forename: Benjamin
authors.initials: B
authors.lastname: Henley
authors.forename: Christine
authors.initials: C
authors.lastname: Hilt
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Bala
authors.initials: B
authors.lastname: Krishnan
authors.forename: Daniel
authors.initials: D
authors.lastname: Kukral
authors.forename: Anne
authors.initials: A
authors.lastname: Lewin
authors.forename: Harold
authors.initials: H
authors.lastname: Malone
authors.forename: Derek
authors.initials: D
authors.lastname: Norris
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: Gregory
authors.initials: G
authors.lastname: Vite
authors.forename: Chiang
authors.initials: C
authors.lastname: Yu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology; D010880:Piperidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010880:Piperidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D014227:Triazines; C552150:BMS-690514