p16INK4a Peptide mimetics identified via virtual screening

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Abstract

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 p16INK4a. Replacement of lost p16INK4a 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 p16INK4a 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.

Original languageEnglish (US)
Pages (from-to)403-405
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Cyclin-dependent kinase
  • Nuclear magnetic resonance
  • Peptide
  • Peptide mimetic
  • Virtual screening

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