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

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