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Cyclin-dependent kinase 5 (CDK5) is a critical regulator of neuronal development and function, whose hyperactivation exacerbates neurodegenerative disorders and certain cancers. While CDK5 is a compelling therapeutic target, achieving selective inhibition is challenging due to high structural homology with cell-cycle CDKs and poor blood-brain barrier penetrance. The article provides the first comprehensive analysis of patented CDK5 inhibitors disclosed between 1999 and 2025. We examine the chemical diversity, selectivity profiles, and therapeutic claims of major chemotypes, including purine analogs (e.g., roscovitine), pyrazole derivatives (e.g., dinaciclib, milciclib), indolobenzazepinones, indirubin derivatives, and emerging modalities such as peptides. Furthermore, we discuss major obstacles such as overcoming off-target toxicity against other CDKs, ensuring sufficient CNS exposure, and identifying reliable biomarkers. Lastly, we speculate on how future success will depend on new strategies such as p25-specific modulation, targeted protein degradation, and advanced delivery systems to translate CDK5′ therapeutic potential into the clinic.
Derzhavina et al. (Tue,) studied this question.