Exploring New Horizons: A Novel Cdk5 Inhibitor Restoring Cognitive Function and Alleviating Type 2 Diabetes

Type 2 diabetes (T2D) is a metabolic disorder frequently associated with cognitive decline, making T2D patients susceptible to dementia. Often referred to as type 3 diabetes, Alzheimer’s disease (AD) shares a close association with hyperglycemia and insulin dysregulation. Despite this, anti-diabetic medications have proven beneficial in reducing cognitive impairment induced by T2D. Previous research, including our own, has highlighted the dysregulation of Cdk5 activity in both T2D and AD, with downstream consequences contributing to the progression of pathophysiological changes in both disorders. Therefore, targeting the kinase Cdk5 may offer a more effective approach to treating T2D and cognitive deterioration. In our study, we present evidence supporting Cdk5 as a significant mediator between T2D and cognitive decline. Through the screening of the KINACore library, we identified novel brain-penetrant Cdk5 inhibitors, BLINK11 and BLINK15. Our study further validated the efficacy of these inhibitors in a high-fat diet-induced T2D model, demonstrating their rescue effects on T2D pathogenesis, including blood glucose levels, obesity, and cognitive impairment as assessed through behavioral studies. Notably, BLINK11 emerges as a promising Cdk5 inhibitor for improving the T2D phenotype and addressing cognitive impairment in T2D conditions. Graphical abstract