Inhibitors for Androgen Receptor Activation Surfaces
Abstract
The androgen receptor (AR) is a proven therapeutic target for treating prostate cancer. Known therapeutics target the ligand binding domain (LBD) at the exact place where dihydrotestosterone (DHT) binds. Upon binding DHT, AR reorganizes to form new interaction surfaces such as the AF2 surface that attracts coregulators. AF2 has been proposed as a second therapeutic target as coactivator recruitment is a key step for AR function. We developed two screening methods to find compounds that bind to AF2. Our method has proved successful with the thyroid receptor. In solution, a competition assay reports coactivator displacement and 3D screening by X-ray crystallography visualizes the compounds on the receptor. Two classes of compounds have been identified that bind to AF2: the first class bind weakly and do not compete with coactivator binding (2-methylindole, and two protein kinase inhibitors), while the second class have micromolar affinity and compete with coactivator binding (TRIAC, and three aspirin derivatives). Screening revealed a significant and undiscovered cryptic surface site that we call binding function 3 (BF3), which might be implicated in AR regulation. These are the first compounds reported to block AR protein-protein interactions and might serve as starting templates for more selective and effective antiandrogens.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2006
- Accession Number
- ADA462434
Entities
People
- Robert J. Fletterick
Organizations
- University of California, San Francisco