title: Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.
abstract: 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.
authors.affiliation: Pfizer Oncology, Groton, Connecticut, USA. robertswg@oncoviarx.com
authors.forename: Walter Gregory
authors.initials: WG
authors.lastname: Roberts
authors.forename: Ethan
authors.initials: E
authors.lastname: Ung
authors.forename: Pamela
authors.initials: P
authors.lastname: Whalen
authors.forename: Beth
authors.initials: B
authors.lastname: Cooper
authors.forename: Catherine
authors.initials: C
authors.lastname: Hulford
authors.forename: Christofer
authors.initials: C
authors.lastname: Autry
authors.forename: Daniel
authors.initials: D
authors.lastname: Richter
authors.forename: Earling
authors.initials: E
authors.lastname: Emerson
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Kath
authors.forename: Kevin
authors.initials: K
authors.lastname: Coleman
authors.forename: Lili
authors.initials: L
authors.lastname: Yao
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Alsina
authors.forename: Marianne
authors.initials: M
authors.lastname: Lorenzen
authors.forename: Martin
authors.initials: M
authors.lastname: Berliner
authors.forename: Michael
authors.initials: M
authors.lastname: Luzzio
authors.forename: Nandini
authors.initials: N
authors.lastname: Patel
authors.forename: Erika
authors.initials: E
authors.lastname: Schmitt
authors.forename: Susan
authors.initials: S
authors.lastname: LaGreca
authors.forename: Jitesh
authors.initials: J
authors.lastname: Jani
authors.forename: Matt
authors.initials: M
authors.lastname: Wessel
authors.forename: Eric
authors.initials: E
authors.lastname: Marr
authors.forename: Matt
authors.initials: M
authors.lastname: Griffor
authors.forename: Felix
authors.initials: F
authors.lastname: Vajdos
mesh_terms: 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
chemical_list: 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