2-Amino-<i>N</i>-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1<i>H</i>-pyrazol-1-yl]-phenyl} Acetamide (OSU-03012), a Celecoxib Derivative, Directly Targets p21-Activated Kinase

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

doi:10.1124/mol.107.037556

Cited by 78 publications

(46 citation statements)

References 40 publications

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“…When exposed to OSU-03012, prostate cancer cells were shown to have dephosphorylation of Akt and subsequent apoptosis (Zhu et al 2004). OSU-03012 was also found in thyroid cancer cells to directly inhibit p-21 activated kinases, downstream effectors of PDK-1, which are important in cell motility and proliferation (Porchia et al 2007). …”

Section: -Phosphoinositide-dependent Kinase-1 Inhibitorsmentioning

confidence: 99%

New therapeutic advances in the management of progressive thyroid cancer

Woyach¹,

Shah²

2009

Endocrine-Related Cancer

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The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodinerefractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I-III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

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Section: -Phosphoinositide-dependent Kinase-1 Inhibitorsmentioning

confidence: 99%

New therapeutic advances in the management of progressive thyroid cancer

Woyach¹,

Shah²

2009

Endocrine-Related Cancer

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“…Thus, inhibitors of Pak1 have been suggested as a novel oncologic therapy Nheu et al, 2002). Although no highly selective inhibitors of Pak1 have been reported, several compounds originally identified for their ability to target other kinases also inhibit Pak family members (Eswaran et al, 2007;Nheu et al, 2002;Porchia et al, 2007). Here we report the identification and characterization of a highly selective, non-ATP-competitive inhibitor that targets the autoregulatory mechanism of group I Paks.…”

Section: Introductionmentioning

confidence: 99%

Analysis of p21-Activated Kinase Function in Neurofibromatosis Type 2

Chernoff¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe NF2 product, Merlin, has recently been shown to inhibit p21-activated kinases (Paks), enzymes known to activate cell cycle progression and to induce changes in the actin cytoskeleton. These findings suggest that loss of Pak function might inhibit the abnormal growth and/or movement of cells lacking Merlin. We had proposed two aims: to test if loss of all Pak function affects signaling in NF2-/-cells and to test if Paks are required for tumorigenesis in an NF2 mouse model system. In the third year of this project, we published a manuscript describing the first selective small molecule inhibitor of group A Paks; completed crossing NF2 and Pak1-/-mice into a C3H genetic background; used a retroviral vector to express an enhanced Pak inhibitor (the Pak2 inhibitor domain) in normal and NF2 BBA (dominant negative) mutant mouse fibroblasts, and showed that loss of Pak function impedes NF2-driven cell proliferation and abnormal morphology; and used the same approach in xenograft experiments to show that loss of Pak function reduces NF2-induced tumor formation. With these advances, we have matched and in some cases exceeded our timetable for year three. Chernoff, Jonathan 4 INTRODUCTION:The goal of this project is to determine if group A p21-activated kinases (Paks) are important elements in signaling in neurofibromatosis type II (NF2). Our hypothesis is that inactivation of the NF2 gene disrupts a signaling pathway emanating from the small GTPase Rac and its effector, p21-activated kinase (Pak). We propose that stimulation of the Rac/Pak signaling axis in cells lacking Merlin leads to changes in transcriptional activity and cytoskeletal dynamics, ultimately resulting in enhanced cell proliferation and motility, which are hallmarks of tumorigenesis. If this hypothesis is correct, then inhibition of Pak signaling should disable the growth advantages of cells lacking Merlin. We intend to test this theory using Pak loss-of-function cells and animals. BODY:We s...

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“…Several other compounds, originally identified for their ability to target other kinases, also inhibit PAK family members [9][10][11]. For example, OSU-03012, a previously characterized PDK1 inhibitor derived from celecoxib was shown to inhibit PAK activity and compete with ATP binding [11]. However, their use as a PAK inhibitor is limited due to their non-selective effects.…”

mentioning

confidence: 99%

“…IPA-3 binds covalently to the PAK1 regulatory domain and prevents binding to its upstream activator Rac/Cdc42 [5]. Several other compounds, originally identified for their ability to target other kinases, also inhibit PAK family members [9][10][11]. For example, OSU-03012, a previously characterized PDK1 inhibitor derived from celecoxib was shown to inhibit PAK activity and compete with ATP binding [11].…”

mentioning

confidence: 99%