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

项目总结 随着雄激素受体的进化，雄激素受体70多年来一直是前列腺癌的靶点。 药物治疗从化学去势、小分子抑制合成酶到阻断 双氢睾丸素。尽管这些方法多种多样，但没有一种方法是可接受的 前列腺癌的长期治疗。我们的长期目标是确定饮食和半 合成口山酮可能激发一类新的化合物作为选择性雄激素受体降解剂 (SARD)用于预防和/或治疗前列腺癌，包括抗去势前列腺癌。新的 因为FDA批准了治疗前列腺癌的药物，包括苯扎鲁胺和 阿比特龙可在治疗开始后短短3-6个月内产生耐药性。山竹果是一种丰富的 黄原酮的来源包括α-山竹黄素、甘草素和其他，鉴定了80多种独特的黄原酮。 从9种口山酮中筛选出α-芒果糖苷和没食子酸作为评价口山酮类化合物的初步研究对象 SARD。使用一种结合天然产物化学分离的方法，我们将创造4种不同的 山竹提取物中含有不同的口山酮。我们将对这些提取物进行充分的化学表征和 AR和AR剪接变异体(即包括AR-V7作为抗性标志)的体外降解机理 体内和药代动力学特性，包括给药参数、微粒体分析和P450 互动。我们的中心假设是山竹属植物衍生的Xanthone是与AR结合的SARD 防止AR的核转位和二聚化。此外，所选的xanthone可抑制激活酶。 已被证明可以在翻译后修改AR。这会导致导致增殖的减少。 内质网应激。内质网应激的标志分子伴侣蛋白Bip被激活 并直接与AR结合，导致野生型AR和AR-V7(AR的剪接变体)的蛋白降解 负责抗雄激素抵抗)。我们在这项提议中的目标是找出最好的 广泛应用于从诊断到去势的前列腺癌发生连续体 抵抗前列腺癌，类似于用于治疗前列腺癌的抗雌激素药物。具体目标1.澄清 α-山竹红素和甘露糖如何破坏雄激素受体的功能和向核内的移位 导致雄激素受体的蛋白酶体降解。具体目标2.确定最活跃的 山竹提取物对AR降解的干扰作用，使用异种小鼠模型，同时表征 口沙酮的药代动力学参数。具体目标3.确定口服明确定义的 山竹果提取物抑制LG-PIN向HG-PIN转化为前列腺癌的实验研究 通过干扰AR。

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.