Cyclin/CDK inhibition in cancer therapy: from small molecules and macrocycles to advanced drug delivery systems

Abstract

Cyclin-CDK complexes have attracted growing interest as therapeutic targets due to their crucial role in cell cycle regulation and their application in cancer treatment. Moreover, although CDKs were considered downstream effectors of the DNA damage response (DDR), several evidence have demonstrated that they act upstream DDR and can represent some of earliest kinases activated inresponse to DNA damage. In this context, recently, the development and application of CDK inhibitors have gained considerable attention. Cyclin-CDK complexes participate in a highly intricate network of protein-protein interactions (PPIs), posing significant challenges for conventional drug strategies. Small molecules and macrocycles represent two classes of compounds of great interest for modulating CDK activity. Small molecules have so far dominated the pharmaceutical landscape given their favorable chemical-physical properties, oral availability, and ability to target well-defined binding sites, leading to the development of several clinically approved CDK inhibitors. Despite their therapeutic importance, CDK inhibitors may still be limited by poor solubility and suboptimal biodistribution, along with off-target toxicity. These limitations have sparked growing interest in drug delivery systems (DDS) as tools to improve pharmacokinetic behavior, increase tumor accumulation, reduce systemic toxicity, and potentially broaden the clinical applicability of CDK inhibitors. Here we discuss the role of cyclin/CDK inhibitors in cancer therapy, with a particular emphasis on the potential advantages offered by drug delivery systems (DDSs) in improving their efficacy and clinical application.