MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

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

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.107.037556v1
72/5/1124    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Porchia, L. M.
Right arrow Articles by Ringel, M. D
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Porchia, L. M.
Right arrow Articles by Ringel, M. D


Received for publication April 30, 2007.
Revised August 2, 2007.
Accepted for publication August 2, 2007.

OSU03012, A Celecoxib Derivative, Directly Targets p21 Activated Kinase

Leonardo M. Porchia 1, Marcy Guerra 1, Yu-Chieh Wang 1, Yunlong Zhang 1, Allan V Espinosa 1, Motoo Shinohara 1, Samuel K Kulp 1, Lawrence S Kirschner 1, Motoyasu Saji 1, Ching-Shih Chen 1, Matthew D Ringel 1*

1 Ohio State University

* Address correspondence to: E-mail: matthew.ringel{at}osumc.edu

Abstract

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 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. Unexpectedly, OSU-03012 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 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.


Key words: Protein Kinases (other), Cdc42, rho, rac, other small G proteins, Metastasis


This article has been cited by other articles:


Home page
 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.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics