Dynamic, Structure Driven Fragment Based Design of Selective Androgen Modulators

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DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, which overcome the ability of all prostate cancers to evolve resistance to current antiandrogen drugs. These changes lead to a poor prognosis and represent a major clinical challenge to the successful treatment of advanced prostate cancer. Prostate cancer (PC) requires the androgen receptor (AR) for growth and proliferation. We will target this receptor as do current marketed antiandrogen drugs. Current drugs all bind to the hormone-binding site (HBS) of AR where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2). A third site has recently been identified -- the BF-3 site -- which, analogous to the hormone site, allosterically affects coactivator binding at the AF-2 site. (The latter allosterically enhances coactivator binding, while ligands at the BF-3 appear to be a negative control). We will exploit this unusual multiplicity of sites in a single drug target to carry out a fragment-based, multi-site, drug discovery strategy that leverages the experimental and theoretical efforts and provides new mechanistic approaches to overcoming advanced PC. To this end we will integrate in silico induced-fit docking with cell based transcription and proliferation assays, X-ray crystallography, and molecular dynamics (MD) simulations to find confirmed hits (X-ray and assays) and determine both structural and dynamic design criteria for lead optimization of compounds at these sites. Project Narrative: The long term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, that overcome the ability of prostate cancers to evolve resistance to current drugs within a few years of treatment. Because, there are currently no drugs effective against this advanced form of the disease, prostate cancer is the second leading cause of cancer deaths in men.