p16^INK4a Peptide mimetics identified via virtual screening

The transition from G1 to S phase in the cell cycle is highly regulated by Cdk4 and Cdk6, which in turn is inhibited by the tumor suppressor p16^INK4a. Replacement of lost p16^INK4a activity in cancer cells via gene therapy has worked in vivo to decrease tumor progression; however, practical issues limit gene therapy applications at this time. Here, we report the discovery of compounds that inhibit Cdk4 and Cdk6 activity. The NMR structure of a peptide that exhibits p16^INK4a activity was solved and combined with known functional data to generate a pharmacophore that was used to mine the NCI chemical database. The hits were filtered utilizing the program Qikprop. Four compounds were subsequently shown to inhibit Cdk4 and/or Cdk6 with IC₅₀ in the μM range. These compounds form lead compounds upon which further cell cycle inhibitors can be developed.