Progress with polo-like kinase (PLK) inhibitors: a patent review (2018–present)

ABSTRACT

Introduction

Polo-like kinases (PLKs) have five isoforms, all of which play crucial roles in cell cycle and cell proliferation, offering opportunities for drug design and treatment of cancers and other related diseases. Notably, PLK1 and PLK4 have been extensively investigated as cancer drug targets. One distinctive feature of PLKs is the presence of a unique polo-box domain (PBD), which regulates kinase activity and subcellular localization. This provides possibilities for specifically targeting PLKs.

Area covered

This article provides an overview of the roles of PLKs in various cancers and related diseases, as well as the drug development involving PLKs, with a particular focus on PLK1 and PLK4. It summarizes the PLK1 and PLK4 inhibitors that have been disclosed in patents or literature (from 2018 – present), which were sourced from SciFinder and WIPO database.

Expert opinion

After two decades of drug development on PLKs, several drugs progressed into clinical trials for the treatment of many cancers; however, none of them has been approved yet. Further elucidating the mechanisms of PLKs and identifying and developing highly selective ATP-competitive inhibitors, highly potent drug-like PBD inhibitors, degraders, etc. may provide new opportunities for cancer therapy and the treatment for several nononcologic diseases. PLKs inhibition-based combination therapies can be another helpful strategy.

KEYWORDS:

• Cancer therapy
• PBD
• PLK1
• PLK4
• polo-like kinases
• PROTAC
• selectivity

Article highlights

• The five isoforms of the PLK family play crucial roles in cell cycle and are associated with cancers and many other diseases.

• PLKs provide two kinds of pockets, kinase domain and polo-box domain, to identify inhibitors or degraders.

• PLK1 is a promising target to develop anticancer drugs, and lots of PLK1 inhibitors, including ATP- competitive inhibitors, PBD inhibitors, bivalent inhibitors, and PROTACs, have been reported, with several advancing into clinical trials.

• PLK4 is considered as a hallmark of cancer and has emerged as a promising target for the diagnosis and treatment of diverse cancers.

• This patent review focuses on PLK inhibitors, particularly PLK1 and PLK4 inhibitors, as published in the literature and patents from 2018 to the present.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

S Bian & R Zhang: patent research and analysis, writing of the manuscript; J Nie, M Zhu & Z Xie: patent research and analysis; C Liao & Q Wang: patent analysis, writing and revising of the manuscript.

Additional information

Funding

This paper was funded by the Anhui Provincial Natural Science Foundation [2308085MH310] and Anhui Provincial Key Research and Development Project [2022i01020004].