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首页> 外文期刊>BMC Chemical Biology >Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility
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Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility

机译：新型蛋白激酶D抑制剂可有效抑制前列腺癌细胞的生长和运动

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Background: Protein kinase D (PKD) has been implicated in a wide range of cellular processes and pathologicalconditions including cancer. However, targeting PKD therapeutically and dissecting PKD-mediated cellular responsesremains difficult due to lack of a potent and selective inhibitor. Previously, we identified a novel pan-PKD inhibitor,CID755673, with potency in the upper nanomolar range and high selectivity for PKD. In an effort to further enhance itsselectivity and potency for potential in vivo application, small molecule analogs of CID755673 were generated bymodifying both the core structure and side-chains.Results: After initial activity screening, five analogs with equal or greater potencies as CID755673 were chosen forfurther analysis: kb-NB142-70, kb-NB165-09, kb-NB165-31, kb-NB165-92, and kb-NB184-02. Our data showed thatmodifications to the aromatic core structure in particular significantly increased potency while retaining highspecificity for PKD. When tested in prostate cancer cells, all compounds inhibited PMA-induced autophosphorylationof PKD1, with kb-NB142-70 being most active. Importantly, these analogs caused a dramatic arrest in cell proliferationaccompanying elevated cytotoxicity when applied to prostate cancer cells. Cell migration and invasion were alsoinhibited by these analogs with varying potencies that correlated to their cellular activity.Conclusions: Throughout the battery of experiments, the compounds kb-NB142-70 and kb-NB165-09 emerged as themost potent and specific analogs in vitro and in cells. These compounds are undergoing further testing for theireffectiveness as pharmacological tools for dissecting PKD function and as potential anti-cancer agents in the treatmentof prostate cancer.
机译：背景：蛋白激酶D（PKD）与多种细胞过程和病理状况（包括癌症）有关。然而，由于缺乏有效和选择性的抑制剂，治疗上靶向PKD和解剖PKD介导的细胞应答仍然困难。以前，我们确定了一种新型的泛PKD抑制剂CID755673，具有较高的纳摩尔浓度范围和对PKD的高选择性。为了进一步提高其在体内应用的选择性和效力，通过修饰核心结构和侧链生成了CID755673的小分子类似物。结果：初步活性筛选后，选择了五个与CID755673相等或更高效力的类似物。进一步分析：kb-NB142-70，kb-NB165-09，kb-NB165-31，kb-NB165-92和kb-NB184-02。我们的数据表明，对芳香族核心结构的修饰特别显着提高了效力，同时保留了对PKD的高特异性。在前列腺癌细胞中测试时，所有化合物均抑制PMA诱导的PKD1自身磷酸化，其中kb-NB142-70最活跃。重要的是，当应用于前列腺癌细胞时，这些类似物引起细胞增殖的急剧停滞，伴随细胞毒性的升高。结论：在整个实验过程中，化合物kb-NB142-70和kb-NB165-09在体外和体外均表现出最强效和特异性。在细胞中。这些化合物作为剖析PKD功能的药理学工具以及作为治疗前列腺癌的潜在抗癌药的有效性，正在接受进一步的测试。

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