New Pyrazolopyrimidine Inhibitors of Protein Kinase D as Potent Anticancer Agents for Prostate Cancer Cells

摘要: The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe identification, in vitro characterization, structure-activity analysis, biological evaluation novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 IKK-16 were identified pan-PKD inhibitors small-scale targeted inhibitor library assay. Both screening hits inhibited isoforms at about 100 nM ATP-competitive Analysis related kinases indicated that was highly selective compared to IKK-16. SAR analysis showed considerably more potent distinct substituent effects pyrazolopyrimidine core. cell-active, potently blocked prostate cell proliferation inducing G2/M arrest. It also migration invasion cells, demonstrating promising anticancer activities on multiple fronts. Overexpression PKD1 or PKD3 almost completely reversed growth arrest inhibition tumor caused 1-NA-PP1, indicating its anti-proliferative anti-invasive mediated through PKD. Interestingly, 12-fold increase sensitivity could be achieved engineering gatekeeper mutation active site PKD1, suggesting paired with analog-sensitive PKD1M659G dissecting PKD-specific functions signaling pathways various systems.