Discovery of Novel and Selective CDK4/6 Inhibitors By Pharmacophore and structure-based Virtual Screening

Abstract

<b>Aim:</b> CDK4 and 6 are the key initiators in the transition from G1 to S phase in the cell cycle; thus, inhibition of CDK4/6 is a promising strategy for cancer treatment. <b>Materials & methods:</b> The Specs database and an in-house library were screened via the pharmacophore model and LibDock protocol and then the retrieved hits were clustered into 100 clusters. The CDK4/6 inhibitory activity of selected compounds was evaluated by CDK enzymatic assays, followed by chemical optimization of the top hit compound. <b>Results & conclusion:</b> The integration of pharmacophores and molecular docking offered us an effective method to discover the novel CDK4/6 inhibitor <b>10</b> and further chemical optimization led to the highly selective and potent CDK4/6 inhibitor <b>18</b>, which exhibited potential for the treatment of multiple myeloma.