Structure-based Design of Cdk4/6-Specific Inhibitors
Annual rept. 30 Sep 2004-29 Sep 2005
PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
Pagination or Media Count:
The CDk46 kinase has elevated activity in spontaneous breast cancer, making it an excellent candidate for targeted inhibition for the treatment of breast cancer. We propose to prepare a CDK46-specific kinase inhibitor that is based on the naturally occurring CDK46 specific inhibitory proteins of the INK4 family. Since the INK4 proteins are notoriously unstable, we have been working towards the preparation and structural characterization of INK4 proteins with improved thermostability that could be used as a scaffold to prepare peptide sub-fragments that may serve as a scaffold to prepare small molecule CDK46- specific inhibitory. During the funding period, we have successfully prepared p18INK4c and p16INK4a proteins with increased thermostability and have characterized the structure of a subset of the more thermostable p18INK4c proteins. Crystallization of a more thermostable p16INK4a protein HTM-p16INK4a is in progress. In the coming year, we will prepare crystals of HTM- p16INK4a that are suitable for X-ray structure determination, characterize its structure using X-ray crystallography and use the structure as a scaffold for the preparation of small molecule CDK416-specific inhibitors that may be useful for the treatment of breast cancer.
- Anatomy and Physiology