Evaluation of Molecular Inhibitors of the c-Myc Oncoprotein
Abstract
We have previously identified seven low molecular weight compounds that inhibit the interaction between the c-Myc oncoprotein and its obligate heterodimerization partner, Max. This occurs as a consequence of the compounds binding directly to c-Myc and blocking its association with Max. These compounds thus prevent the growth of c-Myc over-expressing cells and inhibit their growth as in vivo tumors. However, they are of relatively low potency and cannot be considered to be clinically useful at the current time. Over the past year, we have begun to introduce structural modifications into one of these compounds and have developed a series of rules to explain the consequent structure-activity relationships. In one case, these rules have been applied in the design of small libraries of compounds in order to identify structural derivatives of the index compound. In this way, several 2nd generation compounds with approx. 4-fold enhanced potencies have been developed. Over the next year, we aim to continue to improve the potencies of these compounds. In addition, using in vitro mutagenesis plus techniques that allow us to follow binding of these molecules to c-Myc, we will identify the precise amino acid residues in c-Myc necessary for this binding. These studies will set the stage for us to be able to link together two molecules, which bind to distinct sites of c-Myc, thus allowing us to attain synergistic protein binding and improved potency.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2006
- Accession Number
- ADA452745
Entities
People
- Edward Prochownik