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Published on: May 12, 2017
p16(INK4a) Peptide mimetics identified via virtual screening
Mark A Klein1, Kevin H Mayo, Robert A Kratzke
1Research Service, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA. klein062@umn.edu
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 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.
Insights
Researchers discovered new compounds that inhibit Cdk4 and Cdk6, crucial regulators of the cell cycle. These small molecules offer a promising alternative to gene therapy for developing novel cancer treatments by targeting cell proliferation.
Area of Science:
- Molecular Biology
- Medicinal Chemistry
- Cancer Research
Background:
- Cell cycle progression, specifically the G1 to S phase transition, is tightly regulated by Cyclin-Dependent Kinases 4 and 6 (Cdk4/Cdk6).
- The tumor suppressor p16(INK4a) normally inhibits Cdk4/Cdk6 activity, and its loss is implicated in cancer development.
- Gene therapy approaches to restore p16(INK4a) activity have shown promise in reducing tumor progression but face practical limitations.
Purpose of the Study:
- To discover novel small molecule inhibitors of Cdk4 and Cdk6.
- To develop alternative therapeutic strategies for cancer by targeting cell cycle regulators.
Main Methods:
- Utilized a pharmacophore model derived from the structure of a p16(INK4a)-like peptide and functional data.
- Screened the National Cancer Institute (NCI) chemical database using the pharmacophore.
- Filtered potential hits using the Qikprop program.
- Experimentally validated the inhibitory activity of selected compounds against Cdk4 and/or Cdk6.
Main Results:
- Identified four compounds demonstrating inhibitory activity against Cdk4 and/or Cdk6.
- Achieved inhibitory concentrations (IC50) in the low micromolar (µM) range.
- Established these compounds as potential lead structures for further drug development.
Conclusions:
- Discovery of novel Cdk4/Cdk6 inhibitors provides a viable alternative to gene therapy for cancer treatment.
- These lead compounds represent a foundation for developing new cell cycle inhibitors.
- Further optimization of these compounds could lead to effective cancer therapeutics targeting cell proliferation.
