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

Eur J Med Chem. 2020 Nov 1:205:112638. doi: 10.1016/j.ejmech.2020.112638. Epub 2020 Jul 29.

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.

Keywords: 1-NM-PP1; 3-IN-PP1; Anticancer agents; Protein kinase D inhibitor; Pyrazolo[3,4-d]pyrimidines.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Design*
  • Humans
  • Inhibitory Concentration 50
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • pyrazole
  • protein kinase D
  • Protein Kinase C
  • pyrimidine