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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, Salamoun JM, Carder EJ, Farber E, Xu S, Deng F, Tang H, Wipf P, Wang QJ - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.

ABSTRACT
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.

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Scope of first-generation SAR studies on SD-208.2-Zone model for SD-208 analog synthesis.
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pone.0119346.g002: Scope of first-generation SAR studies on SD-208.2-Zone model for SD-208 analog synthesis.

Mentions: Our approach to the synthetic studies, as detailed in S1 Fig., was based on two zones of substitution in SD-208, where the 2-fluoro-5-chlorobenzene represents zone 1 and 4-aminopyridine represents zone 2 (Fig. 2). Using the pteridine core as a synthetic platform, we were interested in exploring the substitutions attached to the fused pyrimidine ring, specifically to identify the SAR contributions of the fluorine and chlorine substituents in zone 1 and the pyridine ring in zone 2. The secondary amine in zone 2 was preserved because amino substitutions alpha to nitrogen atoms in heterocycles are often implicated in protein kinase hinge binding [27,28]. As a consequence, the secondary amine may prove essential for activity.


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, Salamoun JM, Carder EJ, Farber E, Xu S, Deng F, Tang H, Wipf P, Wang QJ - PLoS ONE (2015)

Scope of first-generation SAR studies on SD-208.2-Zone model for SD-208 analog synthesis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352033&req=5

pone.0119346.g002: Scope of first-generation SAR studies on SD-208.2-Zone model for SD-208 analog synthesis.
Mentions: Our approach to the synthetic studies, as detailed in S1 Fig., was based on two zones of substitution in SD-208, where the 2-fluoro-5-chlorobenzene represents zone 1 and 4-aminopyridine represents zone 2 (Fig. 2). Using the pteridine core as a synthetic platform, we were interested in exploring the substitutions attached to the fused pyrimidine ring, specifically to identify the SAR contributions of the fluorine and chlorine substituents in zone 1 and the pyridine ring in zone 2. The secondary amine in zone 2 was preserved because amino substitutions alpha to nitrogen atoms in heterocycles are often implicated in protein kinase hinge binding [27,28]. As a consequence, the secondary amine may prove essential for activity.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15261, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus