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

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

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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