3BZ3

Crystal Structure Analysis of Focal Adhesion Kinase with a Methanesulfonamide Diaminopyrimidine Inhibitor

Summary for 3BZ3

• Entry DOI: 10.2210/pdb3bz3/pdb
• Descriptor: Focal adhesion kinase 1, N-methyl-N-{3-[({2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}methanesulfonamide (3 entities in total)
• Functional Keywords: kinase, dfg-helix, acetylation, alternative splicing, atp-binding, cell junction, nucleotide-binding, phosphoprotein, transferase, tyrosine-protein kinase
• Biological source: Homo sapiens (human)
• Cellular location: Cell junction, focal adhesion: Q05397
• Total number of polymer chains: 1
• Total formula weight: 32265.15

Authors

Vajdos, F.,Marr, E. (deposition date: 2008-01-17, release date: 2008-04-01, Last modification date: 2024-10-30)

Primary citation

Roberts, W.G.,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.
Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.
Cancer Res., 68:1935-1944, 2008

PubMed 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.

PubMed: 18339875
DOI: 10.1158/0008-5472.CAN-07-5155

Experimental method

X-RAY DIFFRACTION (2.2 Å)