Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.
Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.
Roberts
Walter Gregory
WG
Pfizer Oncology, Groton, Connecticut, USA. robertswg@oncoviarx.com
Ung
Ethan
E
Whalen
Pamela
P
Cooper
Beth
B
Hulford
Catherine
C
Autry
Christofer
C
Richter
Daniel
D
Emerson
Earling
E
Lin
Jing
J
Kath
John
J
Coleman
Kevin
K
Yao
Lili
L
Martinez-Alsina
Luis
L
Lorenzen
Marianne
M
Berliner
Martin
M
Luzzio
Michael
M
Patel
Nandini
N
Schmitt
Erika
E
LaGreca
Susan
S
Jani
Jitesh
J
Wessel
Matt
M
Marr
Eric
E
Griffor
Matt
M
Vajdos
Felix
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D051416:Focal Adhesion Protein-Tyrosine Kinases