PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

Abstract

Simple Summary Cancer is a major public health problem worldwide, and addressing its morbidity, mortality, and prevalence is the first step towards appropriate control measures. Over the past several decades, many pharmacologists have worked to identify anti-cancer targets and drug development strategies. Within this timeframe, many natural compounds have been developed to inhibit cancer growth by targeting kinases, such as AKT, AURKA, and TOPK. Kinase assays and computer modeling are considered to be effective and powerful tools for target screening, as they can predict physical interactions between small molecules and their bio-molecular targets. In the present review, we summarize the inhibitors and compounds that target TOPK and describe its role in cancer progression. The extensive body of research that has investigated the contribution of TOPK to cancer suggests that it may be a promising target for cancer therapy. 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. Abnormal 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 development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates 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.