Stafford Jessy M, Wyatt Michael D, McInnes Campbell
Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, USA.
Expert Opin Drug Discov. 2023 Jan;18(1):65-81. doi: 10.1080/17460441.2023.2159942. Epub 2023 Jan 1.
Polo Like Kinase 1 (PLK1) is a key regulator of mitosis and its overexpression is frequently observed in a wide variety of human cancers, while often being associated with poor survival rates. Therefore, it is considered a potential and attractive target for cancer therapeutic development. The Polo like kinase family is characterized by the presence of a unique C terminal polobox domain (PBD) involved in regulating kinase activity and subcellular localization. Among the two functionally essential, druggable sites with distinct properties that PLK1 offers, targeting the PBD presents an alternative approach for therapeutic development.
Significant progress has been made in progressing from the peptidic PBD inhibitors first identified, to peptidomimetic and recently drug-like small molecules. In this review, the rationale for targeting the PBD over the ATP binding site is discussed, along with recent progress, challenges, and outlook.
The PBD has emerged as a viable alternative target for the inhibition of PLK1, and progress has been made in using compounds to elucidate mechanistic aspects of activity regulation and in determining roles of the PBD. Studies have resulted in proof of concept of efficacy suggesting promise for PBD binders in clinical development.
Polo样激酶1（PLK1）是有丝分裂的关键调节因子，在多种人类癌症中经常观察到其过表达，且常与低生存率相关。因此，它被认为是癌症治疗开发的一个潜在且有吸引力的靶点。Polo样激酶家族的特点是存在一个独特的C末端Polo盒结构域（PBD），该结构域参与调节激酶活性和亚细胞定位。在PLK1提供的两个功能上至关重要、具有不同特性的可成药位点中，靶向PBD为治疗开发提供了另一种方法。
从最初鉴定的肽类PBD抑制剂发展到拟肽类以及最近的类药物小分子，已经取得了显著进展。在这篇综述中，讨论了靶向PBD而非ATP结合位点的基本原理，以及最近的进展、挑战和前景。
PBD已成为抑制PLK1的一个可行替代靶点，在使用化合物阐明活性调节的机制方面以及确定PBD的作用方面都取得了进展。研究已经证明了疗效的概念验证，表明PBD结合剂在临床开发中具有前景。
