Structure-Based Approach for Discovery of Small Molecule Inhibitors Targeted at Bcl-2
Abstract
Overexpression of Bcl-2 has been observed in 70% of breast carcinomas and the expression levels of Bcl-2 proteins correlate with resistance to a wide spectrum of chemotherapeutic drugs and radiation therapy. In this IDEA grant, we propose an effective structure-based approach to discover small molecule inhibitors of Bcl-2 through structure-based 3D-database search over large chemical databases containing >500,000 structurally diverse, non-peptide, drug-like synthetic compounds or natural products. Using this powerful approach, we have discovered 6 classes of structurally diverse, non-peptidic, drug-like, small-molecule inhibitors of Bcl-2. Our studies also showed that the most promising small-molecule inhibitors of Bcl-2 we have discovered potently bind to Bcl-2 protein, inhibit cell growth and induce apoptosis in breast cancer cells with high levels of Bcl-2 proteins and display good selectivity in cancer cells with low levels of Bcl-2 proteins.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA421629
Entities
People
- Shaomeng Wang
Organizations
- University of Michigan