Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor Growth in Vivo by inducing G2/M cell cycle arrest

Tandon, M and Salamoun, JM and Carder, EJ and Farber, E and Xu, S and Deng, F and Tang, H and Wipf, P and Wang, QJ (2015) SD-208, a novel protein kinase D inhibitor, blocks prostate cancer cell proliferation and tumor Growth in Vivo by inducing G2/M cell cycle arrest. PLoS ONE, 10 (3).

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (5MB)
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

Abstract

© 2015 Tandon et al. Protein kinase D (PKD) has been implicated in many aspects of tumorigenesis and progression, and is an emerging molecular target for the development of anticancer therapy. Despite recent advancement in the development of potent and selective PKD small molecule inhibitors, the availability of in vivo active PKD inhibitors remains sparse. In this study, we describe the discovery of a novel PKD small molecule inhibitor, SD-208, from a targeted kinase inhibitor library screen, and the synthesis of a series of analogs to probe the structure-activity relationship (SAR) vs. PKD1. SD-208 displayed a narrow SAR profile, was an ATP-competitive pan-PKD inhibitor with low nanomolar potency and was cell active. Targeted inhibition of PKD by SD-208 resulted in potent inhibition of cell proliferation, an effect that could be reversed by overexpressed PKD1 or PKD3. SD-208 also blocked prostate cancer cell survival and invasion, and arrested cells in the G2/M phase of the cell cycle. Mechanistically, SD-208-induced G2/M arrest was accompanied by an increase in levels of p21 in DU145 and PC3 cells as well as elevated phosphorylation of Cdc2 and Cdc25C in DU145 cells. Most importantly, SD-208 given orally for 24 days significantly abrogated the growth of PC3 subcutaneous tumor xenografts in nude mice, which was accompanied by reduced proliferation and increased apoptosis and decreased expression of PKD biomarkers including survivin and Bcl-xL. Our study has identified SD-208 as a novel efficacious PKD small molecule inhibitor, demonstrating the therapeutic potential of targeted inhibition of PKD for prostate cancer treatment.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tandon, Mmat137@pitt.eduMAT137
Salamoun, JM
Carder, EJejc26@pitt.eduEJC26
Farber, E
Xu, S
Deng, F
Tang, H
Wipf, Ppwipf@pitt.eduPWIPF
Wang, QJ
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLanguino, Lucia R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 6 March 2015
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0119346
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
PubMed ID: 25747583
Date Deposited: 12 May 2015 18:11
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/24100

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item