PBK/TOPK: An effective drug target with diverse therapeutic potential

Abstract

T‐lymphokine‐activated killer cell‐originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnor-mal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple‐negative breast cancer, and melanoma, and it is associated with increased develop-ment, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phos-phorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and partici-pates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications.