TY - JOUR
T1 - 2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] -phenyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase
AU - Porchia, Leonardo M.
AU - Guerra, Marcy
AU - Wang, Yu Chieh
AU - Zhang, Yunlong
AU - Espinosa, Allan V.
AU - Shinohara, Motoo
AU - Kulp, Samuel K.
AU - Kirschner, Lawrence S.
AU - Saji, Motoyasu
AU - Chen, Ching Shih
AU - Ringel, Matthew D.
PY - 2007/11
Y1 - 2007/11
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=35549012934&partnerID=8YFLogxK
U2 - 10.1124/mol.107.037556
DO - 10.1124/mol.107.037556
M3 - Article
C2 - 17673571
AN - SCOPUS:35549012934
VL - 72
SP - 1124
EP - 1131
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 5
ER -