Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development

Abstract

Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.

RETRACTED: Circular forms of dedicator of cytokinesis 1 promotes breast cancer progression by derepressing never in mitosis related kinase 2 via sponging miR‐128‐3p

“…Never in mitosis (NIMA) related kinase 2 (NEK2) is a serine/threonine kinase whose overexpression has been reported in multiple malignant cancers such as breast, prostate, lung and ovarian cancers. NEK2 has been implicated in various aspects of malignant transformation including tumorigenesis, drug resistance, and tumor progression, making NEK2 as an unmatched target for the development of anticancer therapies 19 ; NEK2 inhibitors have been proven in the proliferation of cancer cells in vivo and in vitro 20 . However, the question of whether NEK2 exerts an oncogenic function in breast cancer and the underlying upstream and downstream regulatory mechanisms are still unclear.…”

“…NEK2 has been implicated in various aspects of malignant transformation including tumorigenesis, drug resistance, and tumor progression, making NEK2 as an unmatched target for the development of anticancer therapies 19 ; NEK2 inhibitors have been proven in the proliferation of cancer cells in vivo and in vitro. 20 However, the question of whether NEK2 exerts an oncogenic function in breast cancer and the underlying upstream and downstream regulatory mechanisms are still unclear. Elucidating the role of NEK2 in promoting malignant breast cancer could facilitate the development of approaches to breast cancer and NEK2 inhibitors.…”

NEK2 promotes TP53 ubiquitination to enhance the proliferation and migration of TP53 wild-type glioblastoma cells

“…The NIMA-related kinase (NEK) 2, a serine/threonine kinase belonging to the NEK family, exhibits specific localization at the centrosome. It is widely acknowledged as a multifunctional protein involved in regulating various aspects of the cell cycle [6][7][8][9][10]. NEK2 as multiple research studies have consistently observed its increased expression in different types of cancers and its correlation with poor overall survival results [11][12][13][14].…”

“…The NIMA-related kinase (NEK) 2, a serine/threonine kinase belonging to the NEK family, exhibits specific localization at the centrosome [6]. NEK2 is widely acknowledged as a versatile protein involved in the regulation of various aspects of cell cycle, including replication and segregation of centrosomes, stabilization of microtubules, attachment of kinetochores, and activation of the spindle assembly checkpoint [7][8][9][10]. In the realm of scientific academia, there has been considerable focus on the significant involvement of NEK2 in the development of tumors in recent years.…”

Evaluating the Expression and Prognostic Value of Genes Encoding Microtubule-Associated Proteins in Lung Cancer

“…For example, Ispinesib, a KIF11 inhibitor, was evaluated in a phase I clinical trial in breast cancer, although the specific inhibitors for KIF4A and KIF18B are still limited [ 81 ]. While NEK2 inhibitors have been widely established, and the efficacy was tested in both in vitro and in vivo in several types of cancer, including multiple myeloma, leukemia, gastric, colorectal, glioma, breast, and liver cancers, their effect on lung cancer requires further investigation [ 82 ]. As a key target for Parkinson’s disease, inhibitors for LRRK2 have been developed [ 83 ], but the anticancer effect of this inhibitor has not yet been evaluated.…”