Insights into NEK2 inhibitors as antitumor agents: From mechanisms to potential therapeutics

Abstract

NEK2, a serine/threonine protein kinase, is integral to mitotic events such as centrosome duplication and separation, microtubule stabilization, spindle assembly checkpoint, and kinetochore attachment. However, NEK2 overexpression leads to centrosome amplification and chromosomal instability, which are significantly associated with various malignancies, including liver, breast, and non-small cell lung cancer. This overexpression could facilitate tumor development and confer resistance to therapy by promoting aberrant cell division and centrosome amplification. Consequently, inhibiting NEK2 is considered as a promising strategy for oncological therapy. To date, no small molecule NEK2-specific inhibitors have advanced into clinical trials, highlighting the necessity for optimized design and the deployment of innovative technologies. In this review, we will provide a comprehensive summary of the chemical structure, biological functions, and disease associations of NEK2, focusing on the existing NEK2 small molecule inhibitors, especially their structure-activity relationships, limitations, and research strategies. Our objective is to provide valuable insights for the future development of NEK2 inhibitors and analysis of challenges faced in translating these findings into clinical applications.