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Issue 3, 2017
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Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues

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Abstract

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.

Graphical abstract: Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues

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Publication details

The article was received on 02 Dec 2016, accepted on 31 Jan 2017 and first published on 09 Feb 2017


Article type: Research Article
DOI: 10.1039/C6MD00675B
Citation: Med. Chem. Commun., 2017,8, 640-646
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    Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues

    K. Verschueren, M. Cobbaut, J. Demaerel, L. Saadah, A. R. D. Voet, J. Van Lint and W. M. De Borggraeve, Med. Chem. Commun., 2017, 8, 640
    DOI: 10.1039/C6MD00675B

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