Therapeutic Intervention of PBK/TOPK: Bridging Cellular Signaling to Drug Discovery.

PBK/TOPK is a serine/threonine kinase belonging to the mitogen-activated protein kinase kinase family, involved in the regulation of cell survival, proliferation, growth, apoptosis, and inflammation response. It is overexpressed in various malignant tumors and participates in chromosome condensation, mitotic progression, and cytokinesis. Aberrant activation of PBK may promote tumor-cell proliferation, survival, local invasion, and metastasis, whereas depletion or inhibition of PBK induces mitotic defects and cytokinesis failure, thereby suppressing tumor-cell growth. These findings support PBK as a molecular target with clear pathological relevance in cancer therapy, although its dysregulated expression extends beyond malignancy. Studies have shown that PBK is also expressed in normal proliferating cells, such as neural progenitor cells and spermatogenic cells, and is markedly upregulated under pathological conditions in cardiac, cerebral, and renal tissues. By regulating key physiological processes, including cell proliferation and self-renewal, it plays a pivotal role in maintaining tissue homeostasis and facilitating injury repair. This review compares PBK kinase inhibition with expression silencing and targeted protein degradation, emphasizing the potential advantages of reversible and dose-titratable catalytic modulation while recognizing that kinase-independent PBK functions may require protein-level depletion. By summarizing the development of PBK inhibitors, this review further suggests that activity-based inhibition may offer superior pharmacological controllability, reversibility, dose adjustability, and translational potential compared with expression-silencing strategies such as RNA interference.