A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo.
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the development and progression of several human cancers and are attractive targets for cancer therapy. PHA-665752 was identified as a small molecule, ATP-competitive, active-site inhibitor of the catalytic activity of c-Met kinase (K(i) 4 nM). PHA-665752 also exhibited >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. In cellular studies, PHA-665752 potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells. In addition, PHA-665752 inhibited HGF-stimulated or constitutive phosphorylation of mediators of downstream signal transduction of c-Met, including Gab-1, extracellular regulated kinase, Akt, signal transducer and activator of transcription 3, phospholipase C gamma, and focal adhesion kinase, in multiple tumor cell lines in a pattern correlating to the phenotypic response of a given tumor cell. In in vivo studies, a single dose of PHA-665752 inhibited c-Met phosphorylation in tumor xenografts for up to 12 h. Inhibition of c-Met phosphorylation was associated with dose-dependent tumor growth inhibition/growth delay over a repeated administration schedule at well-tolerated doses. Interestingly, potent cytoreductive activity was demonstrated in a gastric carcinoma xenograft model. Collectively, these results demonstrate the feasibility of selectively targeting c-Met with ATP-competitive small-molecules and suggest the therapeutic potential of targeting c-Met in human cancers.
Christensen
James G
JG
Preclinical Research and Exploratory Development, SUGEN, Inc., South San Francisco, CA 94080, USA. james.christensen@pfizer.com
Schreck
Randall
R
Burrows
Jon
J
Kuruganti
Poonam
P
Chan
Emily
E
Le
Phuong
P
Chen
Jeffrey
J
Wang
Xueyan
X
Ruslim
Lany
L
Blake
Robert
R
Lipson
Kenneth E
KE
Ramphal
John
J
Do
Steven
S
Cui
Jingrong J
JJ
Cherrington
Julie M
JM
Mendel
Dirk B
DB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013450:Sulfones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D013450:Sulfones; D019859:Proto-Oncogene Proteins c-met