# Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer

> **NIH NIH R37** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $352,420

## Abstract

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.

## Key facts

- **NIH application ID:** 9838161
- **Project number:** 5R37CA227101-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Jeremy James Johnson
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,420
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838161

## Citation

> US National Institutes of Health, RePORTER application 9838161, Defining the role of isoprenylated xanthones from the mangosteen for enhancing degradation of full length and variant forms of androgen receptor in prostate cancer (5R37CA227101-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838161. Licensed CC0.

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