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Potent and selective disruption of protein kinase D functionality by a benzoxoloazepinolone

Sharlow, ER and Giridhar, KV and LaValle, CR and Chen, J and Leimgruber, S and Barrett, R and Bravo-Altamirano, K and Wipf, P and Lazo, JS and Wang, QJ (2008) Potent and selective disruption of protein kinase D functionality by a benzoxoloazepinolone. Journal of Biological Chemistry, 283 (48). 33516 - 33526. ISSN 0021-9258

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Abstract

Protein kinase D (PKD) is a novel family of serine/threonine kinases targeted by the second messenger diacylglycerol. It has been implicated in many important cellular processes and pathological conditions. However, further analysis of PKD in these processes is severely hampered by the lack of a PKD-specific inhibitor that can be readily applied to cells and in animal models. Wenow report the discovery of the first potent and selective cell-active small molecule inhibitor for PKD, benzoxoloazepinolone (CID755673). This inhibitor was identified from the National Institutes of Health small molecule repository library of 196,173 compounds using a human PKD1 (PKCμ)-based fluorescence polarization high throughput screening assay. CID755673 suppressed half of the PKD1 enzyme activity at 182 nM and exhibited selective PKD1 inhibition when compared with AKT, polo-like kinase 1 (PLK1), CDK activating kinase (CAK), CAMKIIα, and three different PKC isoforms. Moreover, it was not competitive with ATP for enzyme inhibition. In cell-based assays, CID755673 blocked phorbol ester-induced endogenous PKD1 activation in LNCaP cells in a concentration-dependent manner. Functionally, CID755673 inhibited the known biological actions of PKD1 including phorbol ester-induced class IIa histone deacetylase 5 nuclear exclusion, vesicular stomatitis virus glycoprotein transport from the Golgi to the plasma membrane, and the ilimaquinone-induced Golgi fragmentation. Moreover, CID755673 inhibited prostate cancer cell proliferation, cell migration, and invasion. In summary, our findings indicate that CID755673 is a potent and selective PKD1 inhibitor with valuable pharmacological and cell biological potential. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sharlow, ER
Giridhar, KV
LaValle, CR
Chen, J
Leimgruber, S
Barrett, R
Bravo-Altamirano, K
Wipf, Ppwipf@pitt.eduPWIPF
Lazo, JS
Wang, QJ
Date: 28 November 2008
Date Type: Publication
Journal or Publication Title: Journal of Biological Chemistry
Volume: 283
Number: 48
Page Range: 33516 - 33526
DOI or Unique Handle: 10.1074/jbc.m805358200
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0021-9258
MeSH Headings: Azepines--chemistry; Azepines--pharmacology; Benzofurans--chemistry; Benzofurans--pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Type 2--antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2--metabolism; Cell Cycle Proteins--antagonists & inhibitors; Cell Cycle Proteins--metabolism; Cell Membrane--enzymology; Cell Movement--drug effects; Cell Proliferation--drug effects; Dose-Response Relationship, Drug; Enzyme Activation--drug effects; Golgi Apparatus--enzymology; HeLa Cells; Humans; Phorbol Esters--pharmacology; Protein Kinase C--antagonists & inhibitors; Protein Kinase C--metabolism; Protein Kinase Inhibitors--chemistry; Protein Kinase Inhibitors--pharmacology; Protein Transport--drug effects; Protein-Serine-Threonine Kinases--antagonists & inhibitors; Protein-Serine-Threonine Kinases--metabolism; Proto-Oncogene Proteins--antagonists & inhibitors; Proto-Oncogene Proteins--metabolism; Receptor Protein-Tyrosine Kinases--antagonists & inhibitors; Receptor Protein-Tyrosine Kinases--metabolism
Other ID: NLM PMC2586241
PubMed Central ID: PMC2586241
PubMed ID: 18829454
Date Deposited: 03 Jul 2013 14:55
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/19222

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