Structure-Based Design of CDK4-Specific Inhibitors
Abstract
The inability to inhibit the activity of CDK4/6 kinase is implicated in a significant number of breast cancers, making it an ideal molecule for targeted inhibition. We propose to prepare CDK4/6-specific inhibitors that are based on the naturally occurring CDK4/6 specific inhibitory protein. p18INK4c. Towards this goal, we have used structure-based-design to successfully prepare three mutant p18INK4c proteins, F7IN, F82Q, and F92N, with increased stability. Significantly, the F17N mutant also shows enhanced CDK6 interaction and cell cycle inhibitory activity in vivo. We are currently preparing other mutations at positions 71, 82 and 92 of p18INK4c to generate even more potent CDK4/6 inhibitors. Once this analysis is complete we will combine favorable mutants to create a "super stable" p18INK4c protein that will be used as a scaffold to prepare small peptides derived from the optimally modified p18INK4c protein. The preparation of this initial peptide will than lead to a set of lead peptides or non-peptidic compounds that can be further developed using combinatorial chemistry approaches. High affinity compounds developed through this approach can then be tested in cell culture systems and ultimately through clinical trials to treat CDK4/6-mediated breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2004
- Accession Number
- ADA433997
Entities
People
- Ronen Marmorstein
Organizations
- Wistar Institute