To Degrade or Not Degrade: Targeting the Androgen Receptor in AR-Dependent Prostate Cancer
Abstract
The development and growth of prostate cancer depends on androgens that activate the androgen receptor (AR) in a hormonedependent manner. The research objective is to develop novel anti-cancer drugs based on PROteolysis TArgeting Chimeric molecules (PROTAC), which enhance AR ubiquitination and degradation by the 26S proteasome. During the course of this project, we have used peptide array technology to screen miniaturized libraries of overlapping peptides using the human E3 ubiquitin ligase, C-terminus of Hsc70-Interacting Protein (CHIP), as probe. We have identified a high-affinity CHIP-binding peptide featuring an Arg-Lys-Xxx-Lys-Lys motif, which is found in all steroid hormone receptors, and which was used to synthesize our first AR-targeting PROTAC. We have reconstituted an in vitro ubiquitination assay using highly purified components, which was used, together with a cell based assay, to evaluate our PROTAC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2012
- Accession Number
- ADA560755
Entities
People
- Francis Tsai
Organizations
- Baylor College of Medicine