Cyclin dependent kinase 5 (Cdk5) is a proline dependent serine/threonine kinase expresses primarily in neuronal cells. It regulates cellular migration, microtubule-dynamics and synaptic plasticity. In metabolic tissues, Cdk5 regulates insulin sensitivity and adipogenesis. Although Cdk5 is an essential enzyme in-vivo, its aberrant activation promotes obesity/type-2 diabetes (T2D) and Alzheimer’s disease (AD) via phosphorylation of various proteins including the adipogenic transcription factor PPARg and the tangle-forming protein Tau. Obesity/T2D induced insulin resistance also lead to neurodegeneration, particularly AD, which accounts for 60-80% of dementia cases. Thus targeting Cdk5 may ameliorate these diseases. However, potent and selective inhibitors of Cdk5 are not available. Using virtual screening and structure-activity relationship studies, we identified a novel series of 4-oxo-4,5-dihydrothieno[3,2-c]quinoline compounds as selective ATP non-competitive Cdk5 inhibitors (1) (Chatterjee et al., 2014). In this current endeavor, we demonstrate that the compounds specifically inhibit Cdk5, increase glucose uptake and augment markers of insulin signaling and metabolic pathways in adipocytes. In summary, we discovered novel Cdk5 inhibitors that are active in a cell culture model. Our discovery poses a future therapeutic significance in obesity, diabetes and neurodegenerative diseases.

Efficacy of 4-oxo-4,5-dihydrothieno[3,2-c]quinoline CDK5 inhibitors as modulators of adipogenic insulin/metabolic pathways

2019 Fall National Meeting

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