Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, Protein kinase D inhibitor, Anticancer agents, Pyrazolo[3,4-d]pyrimidines, 3-IN-PP1, 1-NM-PP1, CANCER, GROWTH, POTENT, REGULATOR, DISCOVERY, SUBSTRATE, TARGET, Cell Line, Tumor, Cell Proliferation, Chemistry Techniques, Synthetic, Drug Design, Humans, Inhibitory Concentration 50, Phosphorylation, Protein Kinase C, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, C24/17/074#54270814, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

The multiple roles of protein kinase D (PKD) in various cancer hallmarks have been repeatedly reported. Therefore, the search for novel PKD inhibitors and their evaluation as antitumor agents has gained considerable attention. In this work, novel pyrazolo[3,4-d]pyrimidine based pan-PKD inhibitors with structural variety at position 1 were synthesized and evaluated for biological activity. Starting from 3-IN-PP1, a known PKD inhibitor with IC50 values in the range of 94-108 nM, compound 17m was identified with an improved biochemical inhibitory activity against PKD (IC50 = 17-35 nM). Subsequent cellular assays demonstrated that 3-IN-PP1 and 17m inhibited PKD-dependent cortactin phosphorylation. Furthermore, 3-IN-PP1 displayed potent anti-proliferative activity against PANC-1 cells. Finally, a screening against different cancer cell lines demonstrated that 3-IN-PP1 is a potent and versatile antitumoral agent.