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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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Molecular modeling of SD-208 in the active site of a PKD1 homology model.This depiction demonstrated a potential binding mode of SD208 in the active site of PKD1. Red dotted lines represent key interactions between SD-208 and PKD1.
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pone.0119346.g003: Molecular modeling of SD-208 in the active site of a PKD1 homology model.This depiction demonstrated a potential binding mode of SD208 in the active site of PKD1. Red dotted lines represent key interactions between SD-208 and PKD1.

Mentions: In conjunction with this SAR analysis, we employed our PKD1 homology model [25] to rationally explore a putative binding mode of SD-208 within the active site of PKD1. Common among ATP-competitive inhibitors, SD-208 was shown in Fig. 3A to interact with the hinge region through hydrogen bond formation between the amino acid backbone of Leu662 and its pteridine core. Additionally, a potentially critical hydrogen bond was observed with the nitrogen from the 4-aminopyridine and the charged side chain of Lys612. A similar interaction was also reported in other known PKD1 inhibitors [18]. Our SAR analysis further supports the notion that the nitrogen from the 4-aminopyridine acts as a valuable hydrogen bond acceptor. Ablation of this bond revealed a marked decrease in PKD1 inhibition. Moreover, displayed in Fig. 3B, our model positions the disubstituted phenyl ring in a hydrophobic pocket consisting of Leu589 and Leu713, which may dictate the tolerance of aromatic substitutions. Although other binding modes of SD-208 were explored, the current model best recapitulated results represented in our SAR analysis.


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)

Molecular modeling of SD-208 in the active site of a PKD1 homology model.This depiction demonstrated a potential binding mode of SD208 in the active site of PKD1. Red dotted lines represent key interactions between SD-208 and PKD1.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119346.g003: Molecular modeling of SD-208 in the active site of a PKD1 homology model.This depiction demonstrated a potential binding mode of SD208 in the active site of PKD1. Red dotted lines represent key interactions between SD-208 and PKD1.
Mentions: In conjunction with this SAR analysis, we employed our PKD1 homology model [25] to rationally explore a putative binding mode of SD-208 within the active site of PKD1. Common among ATP-competitive inhibitors, SD-208 was shown in Fig. 3A to interact with the hinge region through hydrogen bond formation between the amino acid backbone of Leu662 and its pteridine core. Additionally, a potentially critical hydrogen bond was observed with the nitrogen from the 4-aminopyridine and the charged side chain of Lys612. A similar interaction was also reported in other known PKD1 inhibitors [18]. Our SAR analysis further supports the notion that the nitrogen from the 4-aminopyridine acts as a valuable hydrogen bond acceptor. Ablation of this bond revealed a marked decrease in PKD1 inhibition. Moreover, displayed in Fig. 3B, our model positions the disubstituted phenyl ring in a hydrophobic pocket consisting of Leu589 and Leu713, which may dictate the tolerance of aromatic substitutions. Although other binding modes of SD-208 were explored, the current model best recapitulated results represented in our SAR analysis.

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