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Ref Type Journal Article
PMID (18339875)
Authors Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, Coleman K, Yao L, Martinez-Alsina L, Lorenzen M, Berliner M, Luzzio M, Patel N, Schmitt E, LaGreca S, Jani J, Wessel M, Marr E, Griffor M, Vajdos F
Title Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.
Journal Cancer research
Vol 68
Issue 6
Date 2008 Mar 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
PF-00562271 PF-562271|PF-562,271|PF-271|VS-6062 FAK inhibitor 13 PF-00562271 is an ATP-competitive inhibitor of FAK and PYK2, which may result in inhibition of cell proliferation and migration, and reduce cell survival (PMID: 18339875, PMID: 23536552, PMID: 22454420).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown glioblastoma multiforme not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor suppression in glioblastoma cancer cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown pancreatic cancer not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor regression in pancreatic cancer cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown Advanced Solid Tumor not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, PF-00562271 inhibited PTK2 (FAK) phosphorylation and growth of multiple tumor cell types in cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown colon cancer not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor regression in colon cancer cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown prostate cancer not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor regression in prostate cancer cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown lung cancer not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor suppression in lung cancer cell line xenograft models (PMID: 18339875). 18339875
Unknown unknown breast cancer not applicable PF-00562271 Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with PF-00562271 inhibited PTK2 (FAK) phosphorylation and resulted in apoptosis and tumor regression in breast cancer cell line xenograft models (PMID: 18339875). 18339875