(260) Computational Model and Synthesis of Selective CDK5/p25 Inhibitors: Pharm.D. student driven outcome

Objective : Cyclin-dependent kinase 5 (Cdk5) is a proline-dependent serine/threonine kinase expressed 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 PPAR-gamma and the tangle-forming protein Tau. Thus targeting Cdk5 may ameliorate these diseases. 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 student-driven endeavor, the objectives of the project were to demonstrate the selectivity of the compounds in CDK5 over CDK2, shown computationally, and to synthesize these compounds for testing in vivo Alzheimer's disease models.

Methods: Computational modeling using the Schrodinger small molecule suite was utilized to demonstrate the selective binding patterns of the compounds in CDK5 compared to CDK2. Syntheses of the identified inhibitors (Chatterjee et al., 2014) were carried out to supply a substantial amount of each of the compounds to be tested in vivo Alzheimer's Disease models in knockout mice and fruit flies.

Results: Compounds were synthesized according to the literature procedure (Chatterjee et al., 2014). Each of the compounds was characterized by 1H NMR and LCMS.

Conclusions: It was a great achievement to involve the Pharm D students in quality drug-discovery research and successfully fulfill the identified objectives. Selectivity of the compounds in the CDK5 model was established and robust syntheses were carried out to obtain the identified selective CDK5 inhibitors.