PT  - JOURNAL ARTICLE
AU  - Leonardo M. Porchia
AU  - Marcy Guerra
AU  - Yu-Chieh Wang
AU  - Yunlong Zhang
AU  - Allan V. Espinosa
AU  - Motoo Shinohara
AU  - Samuel K. Kulp
AU  - Lawrence S. Kirschner
AU  - Motoyasu Saji
AU  - Ching-Shih Chen
AU  - Matthew D. Ringel
TI  - 2-Amino-<em>N</em>-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1<em>H</em>-pyrazol-1-yl]-phenyl} Acetamide (OSU-03012), a Celecoxib Derivative, Directly Targets p21-Activated Kinase
AID  - 10.1124/mol.107.037556
DP  - 2007 Nov 01
TA  - Molecular Pharmacology
PG  - 1124--1131
VI  - 72
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/72/5/1124.short
4100  - http://molpharm.aspetjournals.org/content/72/5/1124.full
SO  - Mol Pharmacol2007 Nov 01; 72
AB  - p21-Activated kinases (PAKs) are regulators of cell motility and proliferation. PAK activity is regulated in part by phosphoinositide-dependent kinase 1 (PDK1). We hypothesized that reduced PAK activity was involved in the effects of 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl} acetamide (OSU-03012), a previously characterized PDK1 inhibitor derived from celecoxib. In three human thyroid cancer cell lines, OSU-03012 inhibited cell proliferation with reduced AKT phosphorylation by PDK1. OSU-03012 unexpectedly inhibited PAK phosphorylation at lower concentrations than PDK1-dependent AKT phosphorylation in two of the three lines. In cell-free kinase assays, OSU-03012 was shown to inhibit PAK activity and compete with ATP binding. In addition, computer modeling predicted a docking site for OSU-03012 in the ATP binding motif of PAK1. Finally, overexpression of constitutively activated PAK1 partially rescued the ability of motile NPA thyroid cancer cells to migrate during OSU-03012 treatment, suggesting that inhibition of PAK may be involved in the cellular effects of OSU-03012 in these cells. In summary, OSU-03012 is a direct inhibitor of PAK, and inhibition of PAK, either directly or indirectly, may be involved in its biological effects in vitro. The American Society for Pharmacology and Experimental Therapeutics