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
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DOI：
10.1016/j.ejmech.2020.112638
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发表时间：
2020-11-01
影响因子：
6.7
通讯作者：
De Borggraeve, Wim M.
中科院分区：
文献类型：
--
作者：
Gilles, Philippe;Kashyap, Rudra S.;De Borggraeve, Wim M.
蛋白激酶D（PKD）在各种癌症标志中的多重作用已被反复报道。因此，寻找新的PKD抑制剂及其作为抗肿瘤剂的评价已获得相当大的关注。在这项工作中，新的吡唑并[3，4-d]嘧啶为基础的泛PKD抑制剂的结构变化的位置1的合成和生物活性进行了评估。从3-IN-PP 1（一种已知的PKD抑制剂，IC 50值在94-108 nM范围内）开始，化合物17 m被鉴定为具有改善的针对PKD的生物化学抑制活性（IC 50 = 17-35 nM）。随后的细胞分析表明，3-IN-PP 1和17 m抑制PKD依赖性coronin磷酸化。此外，3-IN-PP 1对PANC-1细胞显示出有效的抗增殖活性。最后，针对不同癌细胞系的筛选证明3-IN-PP 1是一种有效且通用的抗肿瘤剂。(C)2020 Elsevier Masson SAS。All rights reserved.
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 anti-tumoral agent. (C) 2020 Elsevier Masson SAS. All rights reserved.