Molecular Profiling of EPI-001: An Inhibitor of Androgen Receptor Signaling With a Disputed Mechanism of Action
Abstract
This application is responsive to the Fiscal Year 2014 Prostate Cancer Research Program overarching aim to "develop effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer" and focus area "Therapy: Identification of new targets, pathways, and therapeutic modalities." Prostate cancer (PCa) requires the activity of androgen receptor (AR) for growth and survival. The majority of established drugs to treat PCa target the C-terminal domain of AR. Unfortunately, most of these drugs will eventually fail as tumors evolve into a hormone-independent state, termed castration-resistant prostate cancer (CRPC). Recently, a novel small molecule, EPI-001, was discovered to target AR through a unique mechanism of action, binding to the N-terminal domain. The majority of the cancer-promoting (transcriptional) activity of AR is mediated through the N-terminal domain, and therefore small molecules that target this region of AR may constitute novel therapeutics with activity against CRPC. Recently, studies have suggested that EPI-001 may inhibit AR activity through a different mechanism of action other than N-terminal binding. This project will resolve the mechanism-of-action controversy of EPI-001 by performing activity-associated protein profiling of EPI-001 and related compounds. This chemical biology technique permits an unbiased annotation of all proteins bound by EPI-001, which is mediated through the use of an innovative chemical probe that mimics the candidate drug. Additionally, this technique also helps to identify those proteins bound by EPI-001 that confer its growth inhibitory properties to PCa cells. Consequently, the proposed experiments will (i) elucidate those proteins bound by EPI-001 in PCa that are associated with its growth inhibitory properties and (ii) identify the off-target proteins bound by EPI-001 that may confer toxicity as a result of non-specific binding. It is expected that this study will contribute to the further development of EPI-001 and related compounds as next-generation therapeutics for CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510220
Entities
People
- Daniel A Harki
Organizations
- United States Army
- University of Minnesota