The Polo-like kinases (Plks) are an evolutionary conserved family of Ser/Thr protein kinases that possess, in addition to the classical kinase domain at the N-terminus, a C-terminal polo-box domain (PBD) that binds to phosphorylated proteins and modulates the kinase activity and its localization. Plk1, which regulates the formation of the mitotic spindle, has emerged as a validated drug target for the treatment of cancer, because it is required for numerous types of cancer cells but not for the cell division in noncancer cells. Here, we employed chemical biology methods to investigate the allosteric communication between the PBD and the catalytic domain of Plk1. We identified small compounds that bind to the catalytic domain and inhibit or enhance the interaction of Plk1 with the phosphorylated peptide PoloBoxtide in vitro. In cells, two new allosteric Plk1 inhibitors affected the proliferation of cancer cells in culture and the cell cycle but had distinct phenotypic effects on spindle formation. Both compounds inhibited Plk1 signaling, indicating that they specifically act on Plk1 in cultured cells.

中文翻译：

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小化合物对Plk1中Polo-Box域和催化域之间的变构通讯的调节

Polo样激酶（Plks）是Ser / Thr蛋白激酶的进化保守家族，除了N端的经典激酶结构域外，还具有与磷酸化结合的C末端polo-box结构域（PBD）蛋白质并调节激酶活性及其定位。调节有丝分裂纺锤体形成的Plk1已成为治疗癌症的有效药物靶标，因为它是多种类型癌细胞的必需物质，而不是非癌细胞中细胞分裂的必需物质。在这里，我们采用化学生物学方法来研究PBD和Plk1催化域之间的变构通讯。我们鉴定了与催化结构域结合并抑制或增强Plk1与磷酸化肽PoloBoxtide体外相互作用的小化合物。在细胞中，两种新的变构Plk1抑制剂影响培养物中癌细胞的增殖和细胞周期，但对纺锤体形成具有明显的表型作用。两种化合物均抑制Plk1信号传导，表明它们在培养的细胞中特异性作用于Plk1。