Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyrimidine-based protein kinase D inhibitors

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. [Display omitted] •A novel series of pyrazolo[3,4-d]pyrimidine based PKD inhibitors with structural variety at position 1 was synthesized.•17m showed the most potent pan-PKD inhibitory activity with IC50 values ranging from 17 to 35 nM.•17m and 3-IN-PP1 potently blocked PKD-dependent cortactin phosphorylation in PANC-1 cells.•3-IN-PP1 exhibited low micromolar cytotoxic activity against various cancer cell lines.