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.
Philippe Gilles  1 ,  Rudra S Kashyap  2 ,  Maria João Freitas  2 ,  Sam Ceusters  1 ,  Koen Van Asch  3 ,  Anke Janssens  3 ,  Steven De Jonghe  4 ,  Leentje Persoons  4 ,  Mathias Cobbaut  2 ,  Dirk Daelemans  4 ,  Johan Van Lint  2 ,  Arnout R D Voet  3 ,  Wim M De Borggraeve  5
Affiliations
  • 1. KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium.
  • 2. KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, O&N I Herestraat 49 - Box 901, B-3000, Leuven, Belgium.
  • 3. KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Celestijnenlaan 200G - Box 2403, B-3001, Leuven, Belgium.
  • 4. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49 - Box 1043, B-3000, Leuven, Belgium.
  • 5. KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium. Electronic address: [email protected].
PMID: 32835918 DOI: 10.1016/j.ejmech.2020.112638
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.
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