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.
Highlights
Prostate cancer is the most common male malignancy in western countries [1] and the second leading cause of cancer death in the US, representing 29% of all male cancer deaths [2]
With a cut-off set at 50% inhibition of total protein kinase D1 (PKD1) kinase activity, 16 compounds were identified as primary hits
protein kinase Cs (PKCs)-dependent trans-phosphorylation at Ser738/742 was unaffected by SD-208, indicating that SD-208 directly abrogated PKD1 catalytic activity without blocking upstream PKC-mediated PKD1 trans-phosphorylation
Summary
Prostate cancer is the most common male malignancy in western countries [1] and the second leading cause of cancer death in the US, representing 29% of all male cancer deaths [2]. While localized disease can be treated by a few modalities, the metastatic stage is palliative rather than therapeutic and there are currently no effective therapies. Protein kinase D (PKD) is a family of ubiquitous serine-threonine protein kinase that belongs to the Ca2+/ Calmodulin—dependent protein kinase superfamily [3]. PKDs are activated by protein kinase Cs (PKCs) through phosphorylation of two conserved serine residues in the activation loop of the kinase domain. For PKD1, activation involves PKC-mediated phosphorylation at Ser738 and Ser742 in the activation loop, followed by autophosphorylation at Ser910 that conveys full activation [7,8]
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