Targeting Creatine and Creatine Kinase in Cancer: Exploring Potential Therapeutic Strategies

Creatine kinases (CKs) are a family of vital enzymes implicated in the domain of cellular bioenergy, fulfilling a pivotal role in facilitating the reversible transfer of phosphoryl groups between adenosine triphosphate (ATP) and creatine. This process plays a crucial role in maintaining optimal ATP levels during energy-demanding processes, a requirement that is amplified in rapidly proliferating cells, including cancerous cells. CKs are pivotal in supporting cancer growth and metastasis, making their inhibition a promising therapeutic strategy. The present review discusses a few ways of disrupting the creatine energy production cycle with emphasis on three main areas of research: First, we consider the different strategies that attack the Creatine Transporter (SLC6A8). Since this transporter facilitates the entry of creatine into the cell, it is expected that inhibiting this transporter may lead to reduced availability of creatine for CK-mediated energy production. Second, strategies aimed at directly inhibiting the enzyme carrying out the creatine phosphorylation are described. Lastly, we consider approaches targeting the backward reaction, i.e., the re-conversion of phosphocreatine to creatine and, thereby, the equilibrium of the CK reaction. The current review gives an overview of the structure-activity and structure-property relationships of the currently available CK inhibitors. Understanding these relations in depth is a prerequisite for developing new and more potent and selective CK inhibitors. This review focuses on an in-depth analysis to create better CK inhibitors with possible applications in oncology.