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 IC(50) in the muM range. These compounds form lead compounds upon which further cell cycle inhibitors can be developed.
Klein
Mark A
MA
Research Service, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. klein062@umn.edu
Mayo
Kevin H
KH
Kratzke
Robert A
RA
D000595:Amino Acid Sequence; D001665:Binding Sites; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D016193:G1 Phase; D009682:Magnetic Resonance Spectroscopy; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D016196:S Phase; D013816:Thermodynamics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010455:Peptides; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6