Verschueren Klaas, Cobbaut Mathias, Demaerel Joachim, Saadah Lina, Voet Arnout R D, Van Lint Johan, De Borggraeve Wim M
Department of Chemistry , Molecular Design and Synthesis , KU Leuven , Celestijnenlaan 200F , 3001 Leuven , Belgium . Email:
Department of Cellular and Molecular Medicine , Laboratory of Protein Phosphorylation and Proteomics , KU Leuven , Herestraat 49 box 901 , 3000 Leuven , Belgium.
Medchemcomm. 2017 Mar 1;8(3):640-646. doi: 10.1039/c6md00675b. Epub 2017 Feb 9.
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-]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-]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-]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-]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-]pyrmidines.
在本研究中，我们着手基于吡唑并[3,4 - ]嘧啶支架合理优化PKD抑制剂。本研究的先导化合物是1 - NM - PP1，此前我们和其他人发现它能抑制PKD。在我们的筛选中，我们鉴定出一种化合物（3 - IN - PP1），其效力比1 - NM - PP1提高了10倍，为对吡唑并[3,4 - ]嘧啶衍生化合物敏感的激酶的特异性蛋白激酶抑制剂开辟了新的可能性。有趣的是，观察到的构效关系与通常观察到的结合模式不完全一致，在通常观察到的结合模式中，吡唑并[3,4 - ]嘧啶化合物以与PKD的天然配体ATP相似的方式结合。因此，我们提出一种替代的结合模式，即化合物翻转180度。这种基于吡唑并[3,4 - ]嘧啶的化合物可能的替代结合模式可为对吡唑并[3,4 - ]嘧啶敏感的激酶的新型特异性蛋白激酶抑制剂铺平道路。
