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.
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.
Division of Endocrinology, Department of Medicine, the Ohio State University Colleges of Medicine and Pharmacy, Columbus, Ohio, USA.
Leonardo M
LM
Porchia
Marcy
M
Guerra
Yu-Chieh
YC
Wang
Yunlong
Y
Zhang
Allan V
AV
Espinosa
Motoo
M
Shinohara
Samuel K
SK
Kulp
Lawrence S
LS
Kirschner
Motoyasu
M
Saji
Ching-Shih
CS
Chen
Matthew D
MD
Ringel
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000201:enzymology*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; C500894:OSU 03012; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D000068579:Celecoxib