保罗样激酶1（Polo-like kinase 1, Plk1）与恶性肿瘤的发生与发展密切相关，被认为是肿瘤分子靶向治疗中最具潜力的重要靶标之一。目前，针对Plk1激酶结构域（Kinase domain, KD）设计Plk1抑制剂已成为研究热点，其中部分小分子抑制剂已进入Ⅰ/Ⅱ期临床研究并展现出良好的抗癌前景。尽管Plk1 KD结构域抑制剂具有一定的靶标选择性，但鉴于作为ATP结合口袋的KD结构域在众多激酶结构中的高度保守性和易导致交叉耐药等问题，这使开发高选择性的Plk1 KD结构域抑制剂面临极大的挑战。保罗盒结构域（Polo-Box domain, PBD）作为Plk1特有的底物结合域，在调控Plk1的亚细胞定位中具有重要功能，被认为是未来高选择性Plk1抑制剂开发的理想靶标。文中对Plk1 PBD的分子结构、生物学功能和相关抑制剂的研究进展进行了综述和展望，以期为靶向Plk1 PBD结构域抑制剂的分子设计提供有益的借鉴和参考。

Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1’s subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.

国家自然科学基金 (No. 81703546)，安徽省自然科学基金 (No. 1808085QH265)，吉林省科技发展计划项目 (No. 20160520045JH)，安徽省高校自然科学研究重大项目 (No. KJ2019ZD30)，安徽省重点研究与开发计划项目 (No. 202004a07020041) 资助。