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

Autor: Gilles P; KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium., Kashyap RS; 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., Freitas MJ; 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., Ceusters S; KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium., Van Asch K; KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Celestijnenlaan 200G - Box 2403, B-3001, Leuven, Belgium., Janssens A; KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Celestijnenlaan 200G - Box 2403, B-3001, Leuven, Belgium., De Jonghe S; 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., Persoons L; 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., Cobbaut M; 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., Daelemans D; 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., Van Lint J; 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., Voet ARD; KU Leuven, Department of Chemistry, Biochemistry, Molecular and Structural Biology, Celestijnenlaan 200G - Box 2403, B-3001, Leuven, Belgium., De Borggraeve WM; KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium. Electronic address: wim.deborggraeve@kuleuven.be.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Nov 01; Vol. 205, pp. 112638. Date of Electronic Publication: 2020 Jul 29.
DOI: 10.1016/j.ejmech.2020.112638
Abstrakt: 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 IC 50 values in the range of 94-108 nM, compound 17m was identified with an improved biochemical inhibitory activity against PKD (IC 50  = 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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