Polo样激酶1（Plk1）是一种在细胞周期进程中有重要调控作用的丝氨酸/苏氨酸蛋白激酶。它的过度表达在多种肿瘤的发生及发展过程中起着关键作用，目前已有多个不同结构的作用于ATP结合口袋和底物结合位点的小分子Plk1抑制剂进入临床研究。Polo box结构域（PBD）是Plks特有的结构域，对Plk1在细胞中的定位及其与底物的结合有重要作用，被认为是另一个靶向型Plk1抑制剂研究的潜在靶点。本课题在前期工作的基础上，对目前已报道的磷酸肽与Plk1的PBD结合的结构信息进行分析和整合，提取磷酸肽与PBD结合的关键结构片段，并利用基于片段的药物设计理念，对这些片段分别进行改造，再通过重新组装和优化设计了一系列以PBD为靶点的基于蛋白-蛋白相互作用的新型Plk1抑制剂。本课题的成功实施，将发展出具有高度亚型选择性并能有效克服肽类化合物缺陷的新型Plk1抑制剂，并为抗肿瘤药物的创新研究提供基础。

Polo-like kinase 1 (Plk1) is a serine/threonine kinase which plays a critical role in the regulation of cell cycle. Its over-expression is critical in the producing and progressing of multiple human tumors and is recognized as an effective target for the development of novel anti-cancer drugs. Currently a couple of small molecules with various structures targeting ATP or substrates binding sites have entered different stages of clinical trials. Polo box domain (PBD) is a unique domain of Plks which plays important roles in the sub-cellular location of Plks and also in the recognition of their substrates, therefore it has become attractive targets for the development of novel target-directed Plk1 inhibitors. Currently, the reported compounds targeting PBD with potent binding affinities are all short peptides or their analogues containing phosphorylated serine/threonine residue. Similar to other peptides, these compounds have their intrinsic drawbacks, such as poor bio-availability and stability. In this project, we identified the fragments in the short peptides and their analogues which are critical to the binding of these compounds to Plk1 by analyzing the reported crystal structures of these peptides or peptidic analogues in complex with the PBD of Plk1 and proposed their modifications and optimizations. Through reorganization and assembling of these fragments, we have designed a series of novel Plk1 inhibitors and proposed their synthesis and biochemical and biological evaluations. Successfully carrying out, our project will lead to the development of potent Plk1 inhibitors which can effectively overcome the drawbacks of the peptides and their analogues.