Polo-like kinase 1-3 (PLK1-3)

Polo-like kinases 1-3 (PLK1-3) are a subgroup of the highly conserved Polo-like kinase family of serine/threonine protein kinases that play essential roles in cell cycle progression and the DNA damage response [1.1.1, 1.1.2]. PLK1 is the most extensively characterized member, acting as a master regulator of mitosis by controlling centrosome maturation, spindle assembly, and cytokinesis [1.2.4, 1.4.1]. In contrast, PLK2 and PLK3 are primarily involved in the DNA damage checkpoint and maintaining genomic stability, often functioning as tumor suppressors [1.1.2, 1.4.3]. PLK1 is frequently overexpressed in a wide range of human malignancies, including leukemias and solid tumors, where its high levels correlate with increased proliferation and poor clinical outcomes [1.2.1, 1.4.1]. Consequently, PLK1-3 have become significant therapeutic targets, with drug development focusing on small-molecule inhibitors that target either the N-terminal catalytic kinase domain or the C-terminal Polo-box domain [1.1.1, 1.2.5]. While these inhibitors, such as Volasertib and BI 2536, show potent anti-tumor activity by inducing mitotic arrest and apoptosis, their clinical use is often limited by dose-limiting toxicities like myelosuppression [1.3.1, 1.4.4]. The development of more selective inhibitors, particularly those targeting the unique Polo-box domain of PLK1, remains an active area of research to improve the therapeutic window [1.1.2, 1.2.5]. Beyond cancer, PLK1-3 are also being investigated for roles in neurodegenerative diseases and viral infections [1.3.1, 1.4.3].

Other names

PLK1PLK2PLK3Polo-like kinase 1Polo-like kinase 2Polo-like kinase 3STPK13SNKFNKPRK

ATP-competitive inhibition of the kinase domain, inhibition of the Polo-box domain (PBD), and substrate-competitive inhibition.