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Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility

Lavalle, CR and Bravo-Altamirano, K and Giridhar, KV and Chen, J and Sharlow, E and Lazo, JS and Wipf, P and Wang, QJ (2010) Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility. BMC Chemical Biology, 10.

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Abstract

Background. Protein kinase D (PKD) has been implicated in a wide range of cellular processes and pathological conditions including cancer. However, targeting PKD therapeutically and dissecting PKD-mediated cellular responses remains difficult due to lack of a potent and selective inhibitor. Previously, we identified a novel pan-PKD inhibitor, CID755673, with potency in the upper nanomolar range and high selectivity for PKD. In an effort to further enhance its selectivity and potency for potential in vivo application, small molecule analogs of CID755673 were generated by modifying both the core structure and side-chains. Results. After initial activity screening, five analogs with equal or greater potencies as CID755673 were chosen for further analysis: kb-NB142-70, kb-NB165-09, kb-NB165-31, kb-NB165-92, and kb-NB184-02. Our data showed that modifications to the aromatic core structure in particular significantly increased potency while retaining high specificity for PKD. When tested in prostate cancer cells, all compounds inhibited PMA-induced autophosphorylation of PKD1, with kb-NB142-70 being most active. Importantly, these analogs caused a dramatic arrest in cell proliferation accompanying elevated cytotoxicity when applied to prostate cancer cells. Cell migration and invasion were also inhibited by these analogs with varying potencies that correlated to their cellular activity. Conclusions. Throughout the battery of experiments, the compounds kb-NB142-70 and kb-NB165-09 emerged as the most potent and specific analogs in vitro and in cells. These compounds are undergoing further testing for their effectiveness as pharmacological tools for dissecting PKD function and as potential anti-cancer agents in the treatment of prostate cancer. © 2010 LaValle et al; licensee BioMed Central Ltd.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lavalle, CR
Bravo-Altamirano, K
Giridhar, KV
Chen, J
Sharlow, E
Lazo, JS
Wipf, Ppwipf@pitt.eduPWIPF
Wang, QJqjw1@pitt.eduQJW1
Date: 6 May 2010
Date Type: Publication
Journal or Publication Title: BMC Chemical Biology
Volume: 10
DOI or Unique Handle: 10.1186/1472-6769-10-5
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
Other ID: NLM PMC2873968
PubMed Central ID: PMC2873968
PubMed ID: 20444281
Date Deposited: 18 Jul 2014 21:18
Last Modified: 31 Jul 2020 17:00
URI: http://d-scholarship.pitt.edu/id/eprint/22227

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