Structure-Based Design of Molecules to Reactivate Tumor Derived p53 Mutations
Abstract
Of the genetic alterations associated with breast cancer, changes in p53 are the most frequent and identified. The overall goal of our studies is to identify small molecule compounds that bind and stabilize the subset of tumor-derived p53 mutants. We anticipate that the identification of such compounds will serve as a scaffold for the preparation of small molecule drugs for the treatment of p53-mediated breast cancer. Towards our goal we have employed a Multiple Solvent Crystal Stmctures (MSCS) technique to identify p53 binding sites for the small molecule compounds Tris and Isopropanol. The X-ray crystal structure of both complexes suggests that they each may repair a subset of tumor derived p53 mutants. Correlating with this possibility, we have shown that Tris stabilizes p53 stmcture in solution. In the coming year, we will focus on using the p53/isopropanol and p53/Tris complexes as scaffolds for developing high affinity compounds for the rescue of tumor-derived p53 mutations. We will specifically focus on using computational algorithms to screen virtual libraries for compounds that build upon the p53 interactions made by isopropanol and Tris compounds. Compounds that show favorable properties will be characterized both structurally and flinctionally.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2005
- Accession Number
- ADA437665
Entities
People
- Ronen Marmorstein
Organizations
- University of Pennsylvania