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Molecular Pharmacology Fast Forward
First published on August 2, 2007; DOI: 10.1124/mol.107.037556

0026-895X/07/7205-1124-1131$20.00
Mol Pharmacol 72:1124-1131, 2007

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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

Leonardo M. Porchia, Marcy Guerra, Yu-Chieh Wang, Yunlong Zhang, Allan V. Espinosa, Motoo Shinohara, Samuel K. Kulp, Lawrence S. Kirschner, Motoyasu Saji, Ching-Shih Chen, and Matthew D. Ringel

Division of Endocrinology, Department of Medicine (A.V.E., M.S., L.S.K., M.S., M.D.R.), and Division of Medicinal Chemistry and Pharmacognosy (L.M.P., M.G., Y.-C.W., Y.Z., S.K.K., C.-S.C.), the Ohio State University Colleges of Medicine and Pharmacy and the Arthur G. James Comprehensive Cancer Center, Columbus, Ohio

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.

Received April 27, 2007; accepted August 2, 2007

Address correspondence to: Dr. Matthew D. Ringel, 445 D McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210. E-mail: matthew.ringel{at}osumc.edu




This article has been cited by other articles:


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 Molecular Cancer TherapeuticsHome page
S.-C. Weng, Y. Kashida, S. K. Kulp, D. Wang, R. W. Brueggemeier, C. L. Shapiro, and C.-S. Chen
Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor
Mol. Cancer Ther., April 1, 2008; 7(4): 800 - 808.
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