PMID- 17483355
OWN - NLM
STAT- MEDLINE
DCOM- 20070618
LR  - 20220419
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 9
DP  - 2007 May 1
TI  - An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits 
      cytoreductive antitumor efficacy through antiproliferative and antiangiogenic 
      mechanisms.
PG  - 4408-17
AB  - 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.
FAU - Zou, Helen Y
AU  - Zou HY
AD  - Departments of Cancer Biology, Pfizer Global Research and Development, La Jolla 
      Laboratories, La Jolla, California 92121, USA.
FAU - Li, Qiuhua
AU  - Li Q
FAU - Lee, Joseph H
AU  - Lee JH
FAU - Arango, Maria E
AU  - Arango ME
FAU - McDonnell, Scott R
AU  - McDonnell SR
FAU - Yamazaki, Shinji
AU  - Yamazaki S
FAU - Koudriakova, Tatiana B
AU  - Koudriakova TB
FAU - Alton, Gordon
AU  - Alton G
FAU - Cui, Jingrong J
AU  - Cui JJ
FAU - Kung, Pei-Pei
AU  - Kung PP
FAU - Nambu, Mitchell D
AU  - Nambu MD
FAU - Los, Gerrit
AU  - Los G
FAU - Bender, Steven L
AU  - Bender SL
FAU - Mroczkowski, Barbara
AU  - Mroczkowski B
FAU - Christensen, James G
AU  - Christensen JG
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridines)
RN  - 53AH36668S (Crizotinib)
RN  - EC 2.7.10.1 (RON protein)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Angiogenesis Inhibitors/pharmacology
MH  - Animals
MH  - Breast Neoplasms/blood supply/*drug therapy/enzymology/pathology
MH  - Cell Growth Processes/drug effects
MH  - Crizotinib
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Endothelial Cells/drug effects
MH  - Female
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Neovascularization, Pathologic/drug therapy
MH  - Phosphorylation/drug effects
MH  - Piperidines/*pharmacology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Pyrazoles
MH  - Pyridines/*pharmacology
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Signal Transduction/drug effects
MH  - Stomach Neoplasms/blood supply/*drug therapy/enzymology/pathology
MH  - Xenograft Model Antitumor Assays
EDAT- 2007/05/08 09:00
MHDA- 2007/06/19 09:00
CRDT- 2007/05/08 09:00
PHST- 2007/05/08 09:00 [pubmed]
PHST- 2007/06/19 09:00 [medline]
PHST- 2007/05/08 09:00 [entrez]
AID - 67/9/4408 [pii]
AID - 10.1158/0008-5472.CAN-06-4443 [doi]
PST - ppublish
SO  - Cancer Res. 2007 May 1;67(9):4408-17. doi: 10.1158/0008-5472.CAN-06-4443.