Computational Search for Novel Antagonists to the Metastatic Mutant Forms of the Androgen Receptor
Abstract
Prostate cancer is the most common cancer in the United States and is the second leading cause of cancer death among men in most western countries. The activation of androgen receptor is a major factor contributing to progression of the prostate cancer. Therefore, the administration antiadrogens (androgen antagonists) is a vital part of currently used therapies. However, limited number of available antiandrogens, especially those against mutant forms of androgen receptor found in metastatic prostate cancer, affect successful outcome of a treatment. Major factor impeding discovery of novel antiandrogens was absence of crystal structure of androgen receptor in antagonist conformation. To tackle this issue, the model of the receptor in antagonist conformation was built and validated in vitro. The model was used to search for novel non steroidal antiandrogen ligands based on the structures of marketed drugs. Two ligands were identified as promising drug leads, inhibiting transcription of target genes at submicromolar concentration. One of the ligands was found to act mechanistically different from known androgen receptor antagonists.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2006
- Accession Number
- ADA452301
Entities
People
- Anton V. Cheltsov
Organizations
- Scripps Research