Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Export

@article{citeulike:3198072, 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.}, address = {Pfizer Oncology, Groton, Connecticut, USA. robertswg@oncoviarx.com}, author = {Roberts, W. G. and Ung, E. and Whalen, P. and Cooper, B. and Hulford, C. and Autry, C. and Richter, D. and Emerson, E. and Lin, J. and Kath, J. and Coleman, K. and Yao, L. and Martinez-Alsina, L. and Lorenzen, M. and Berliner, M. and Luzzio, M. and Patel, N. and Schmitt, E. and LaGreca, S. and Jani, J. and Wessel, M. and Marr, E. and Griffor, M. and Vajdos, F.}, citeulike-article-id = {3198072}, citeulike-linkout-0 = {http://dx.doi.org/10.1158/0008-5472.CAN-07-5155}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18339875}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18339875}, day = {15}, doi = {10.1158/0008-5472.CAN-07-5155}, issn = {1538-7445}, journal = {Cancer research}, keywords = {cancer, focal\_adhesion\_kinase, tumors}, month = {March}, number = {6}, pages = {1935--1944}, posted-at = {2008-09-05 21:16:52}, priority = {3}, title = {Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-07-5155}, volume = {68}, year = {2008} }

TY - JOUR ID - citeulike:3198072 L3 - citeulike-article-id:3198072 N2 - 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. IS - 6 JF - Cancer research SN - 1538-7445 AD - Pfizer Oncology, Groton, Connecticut, USA. robertswg@oncoviarx.com EP - 1944 TI - Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. VL - 68 SP - 1935 KW - cancer KW - focal_adhesion_kinase KW - tumors AU - Roberts, WG AU - Ung, E AU - Whalen, P AU - Cooper, B AU - Hulford, C AU - Autry, C AU - Richter, D AU - Emerson, E AU - Lin, J AU - Kath, J AU - Coleman, K AU - Yao, L AU - Martinez-Alsina, L AU - Lorenzen, M AU - Berliner, M AU - Luzzio, M AU - Patel, N AU - Schmitt, E AU - LaGreca, S AU - Jani, J AU - Wessel, M AU - Marr, E AU - Griffor, M AU - Vajdos, F PY - 2008/03/15/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-07-5155 ER -