title: An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.
abstract: The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
authors.affiliation: Departments of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California 92121, USA.
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Zou
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Li
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arango
authors.forename: Scott R
authors.initials: SR
authors.lastname: McDonnell
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Koudriakova
authors.forename: Gordon
authors.initials: G
authors.lastname: Alton
authors.forename: Jingrong J
authors.initials: JJ
authors.lastname: Cui
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Nambu
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Steven L
authors.initials: SL
authors.lastname: Bender
authors.forename: Barbara
authors.initials: B
authors.lastname: Mroczkowski
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D000077547:Crizotinib; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases