PROJECT SUMMARY The androgen receptor has been a target of prostate cancer for over 70 years with the evolution of pharmacotherapy ranging from chemical castration, small molecular inhibition of anabolic enzymes, to blockade of dihydrotestosterone. Despite the variety of these approaches none of these approaches are acceptable for long term treatment across the prostate cancer continuum. Our long term goal is to identify dietary and semi- synthetic xanthones that may inspire a new class of compounds as Selective Androgen Receptor Degraders (SARDs) for prevention and/or treatment of prostate cancer including castration resistant prostate cancer. New approaches are needed because FDA approved drugs for prostate cancer including enzalutamide and abiraterone can develop resistance in as little as 3-6 months of therapy initiation. The mangosteen fruit is a rich source of xanthones including α-mangostin, gartanin and others with more than 80 unique xanthones identified. α-Mangostin and gartanin were chosen from 9 xanthones for our preliminary studies to evaluate xanthones as SARDs. Using an approach incorporating natural products chemistry isolation we will create 4 different mangosteen extracts with different xanthones. We will fully characterize these extracts chemically and mechanistically for AR and AR splice variant (i.e. including AR-V7 a marker of resistance) degradation in vitro and in vivo as well as pharmacokinetic properties including dosing parameters, microsome analysis and p450 interactions. Our central hypothesis is that mangosteen derived xanthones are SARDs that bind to the AR preventing the nuclear translocation and dimerization of AR. Additionally, selected xanthones inhibit kinases that have been shown to post-translationally modify AR. This leads to a decrease in proliferation inducing endoplasmic reticulum stress. The chaperone protein BiP, a marker of endoplasmic reticulum stress, is activated and binds AR directly leading to proteolytic degradation of wild type AR and AR-V7 (a splice variant of AR responsible for anti-androgen resistance). Our objective in this proposal is to identify xanthones with the greatest potential for broad application across the prostate carcinogenesis continuum spanning diagnosis to castration resistance prostate cancer similar to anti-estrogens used to treat prostate cancer. Specific Aim 1. Elucidate how α-mangostin and gartanin disrupt the functionality and translocation of the androgen receptor to the nucleus leading to the proteasomal degradation of androgen receptor. Specific Aim 2. Identify the most active mangosteen extract for AR degradation disruption using a xenograft mouse model while characterizing the pharmacokinetic parameters of xanthones. Specific Aim 3. Determine if oral administration of a well-defined mangosteen fruit extract will inhibit the development of LG-PIN to HG-PIN to prostate cancer in TRAMP mice through disruption of AR.