Novel Degraders of the Androgen Receptor (AR) and AR Splice Variants (AR-SVs)

雄激素受体 (AR) 和 AR 剪接变体 (AR-SV) 的新型降解剂

基本信息

项目摘要

Approximately 160,000 men were diagnosed with prostate cancer (PCa) and around 30,000 died of PCa in 2017. Over 3.3 million men are surviving with PCa in the United States and this number is expected to increase to 4.5 million by 2026. Current therapeutic strategies for advanced castration-resistant prostate cancer (CRPC) include androgen receptor (AR) antagonists and a CYP17A1 inhibitor that prevents synthesis of androgens. Although these drugs extend the progression-free survival, approximately 30% of the tumors do not respond to these therapies and the remaining develops resistance shortly after treatment initiation. One of the primary reasons for CRPC relapse, despite these treatments, is expression of constitutively-active AR splice variants (AR-SV) that lack the ligand binding domain (LBD). To overcome this critical barrier, we discovered novel AR antagonists (Selective Androgen Receptor Degraders (SARDs)) that bind to the AR-activation function-1 domain (AF-1) in the N terminal domain (NTD) and/or LBD and antagonize and degrade AR and AR-SVs. The SARDs have unique pharmacologic properties that strongly and selectively antagonize the AR and degrade full length and splice variant AR (independent of LBD) in multiple models. These SARDs inhibit growth of prostate cancer cells and tumors that are dependent on AR full length and splice variants for growth. The SARDs we have tested thus far have poor bioavailability and drug-like properties. In order to overcome the poor bioavailability and to understand the mechanisms of action, we propose a) to develop novel SARDs that will inhibit and degrade full length and splice variants of the AR and will be orally bioavailable and b) to identify mechanisms by which the AR and its splice variants are degraded, resulting in drugs with better efficacy. Under aim-1 we will synthesize AR antagonists belonging to new generation of SARDs that will degrade the AR, inhibit prostate cancer growth, and will be orally bioavailable. We will synthesize and identify orally bioavailable SARDs and evaluate those using in vitro and in vivo PCa and CRPC models. These studies will result in highly potent new SARDs that will have drug-like properties. Under aim-2, we will identify the role of ubiquitination in AR and AR-SV degradation by discerning ubiquitin sites and characterizing their role in AR, AR-SV, and SARD action. Efforts will be dedicated in aim-3 to determine the scavenging role of SARDs and the implications of GATA-2 down-regulation for SARD function. The expected outcome of these studies will be new next generation drugs to treat aggressive CRPC, research tools to study AR degradation, better understanding of the AR and CRPC basic biology, and surrogate endpoints to advance these molecules to clinic.
2017年,约有16万名男性被诊断患有前列腺癌(PCa),约有3万人死于PCa。 在美国,超过330万男性患有PCa,预计这一数字将增加到4.5 到2026年,亿。目前晚期去势抵抗性前列腺癌(CRPC)的治疗策略包括 雄激素受体(AR)拮抗剂和阻止雄激素合成的CYP 17 A1抑制剂。虽然 这些药物延长了无进展生存期,大约30%的肿瘤对这些药物没有反应。 治疗开始后不久,其余的产生耐药性。的主要原因之一 尽管有这些治疗,CRPC复发是组成型活性AR剪接变体(AR-SV)的表达, 缺乏配体结合结构域(LBD)。为了克服这一关键障碍,我们发现了新的AR拮抗剂, (选择性雄激素受体降解物(SARD)),其结合于AR-激活功能-1结构域(AF-1), N末端结构域(NTD)和/或LBD并拮抗和降解AR和AR-SV。SARD拥有独特的 强烈和选择性拮抗AR并降解全长和剪接的药理学性质 多个模型中的变异AR(独立于LBD)。这些SARD抑制前列腺癌细胞的生长, 依赖于AR全长和剪接变体生长的肿瘤。 到目前为止,我们测试的SARD的生物利用度和药物性质都很差。为了克服 差的生物利用度和了解作用机制,我们建议a)开发新的SARD, 将抑制和降解AR的全长和剪接变体,并且将是口服生物可利用的,和B)鉴定 AR及其剪接变体被降解的机制,导致药物具有更好的疗效。下 目的1合成新一代SARD类AR拮抗剂,降解AR,抑制 前列腺癌的生长,并且将是口服生物可利用的。我们将合成和鉴定口服生物可利用的SARD 并使用体外和体内PCa和CRPC模型进行评价。这些研究将产生高效的 新的SARD将具有类似药物的特性。在aim-2中,我们将确定泛素化在AR中的作用, 通过识别泛素位点并表征其在AR、AR-SV和SARD作用中的作用来降解AR-SV。 将致力于目标3,以确定SARD的清除作用和加塔-2的影响 下调SARD功能。这些研究的预期结果将是新的下一代药物 治疗侵袭性CRPC,研究AR降解的研究工具,更好地了解AR和CRPC 基础生物学和替代终点,以将这些分子推向临床。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor.
  • DOI:
    10.1002/anie.202203225
  • 发表时间:
    2022-08-01
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Mitachi, Katsuhiko;Mingle, David;Effah, Wendy;Sanchez-Ruiz, Antonio;Hevener, Kirk E.;Narayanan, Ramesh;Clemons, William M., Jr.;Sarabia, Francisco;Kurosu, Michio
  • 通讯作者:
    Kurosu, Michio
FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways.
FAK PROTAC 通过破坏激酶依赖和独立途径抑制卵巢肿瘤生长和转移
  • DOI:
    10.3389/fonc.2022.851065
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
  • 通讯作者:
An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer.
  • DOI:
    10.3390/ijms22042124
  • 发表时间:
    2021-02-20
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Mohler ML;Sikdar A;Ponnusamy S;Hwang DJ;He Y;Miller DD;Narayanan R
  • 通讯作者:
    Narayanan R
Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.
  • DOI:
    10.1021/acs.jmedchem.2c01858
  • 发表时间:
    2023-03-09
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Hwang, Dong-Jin;He, Yali;Ponnusamy, Suriyan;Thiyagarajan, Thirumagal;Mohler, Michael L.;Narayanan, Ramesh;Miller, Duane D.
  • 通讯作者:
    Miller, Duane D.
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Ramesh Narayanan其他文献

Ramesh Narayanan的其他文献

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{{ truncateString('Ramesh Narayanan', 18)}}的其他基金

Racial Disparity in the Expression of Androgen Receptor Splice Variants (AR-SVs) in Prostate Cancer
前列腺癌中雄激素受体剪接变体 (AR-SV) 表达的种族差异
  • 批准号:
    10099535
  • 财政年份:
    2020
  • 资助金额:
    $ 39.73万
  • 项目类别:
Novel Degraders of Androgen Receptor (AR) and AR Splice Variants (AR-SVs)
雄激素受体 (AR) 和 AR 剪接变体 (AR-SV) 的新型降解剂
  • 批准号:
    10058908
  • 财政年份:
    2019
  • 资助金额:
    $ 39.73万
  • 项目类别:
Novel Degraders of the Androgen Receptor (AR) and AR Splice Variants (AR-SVs)
雄激素受体 (AR) 和 AR 剪接变体 (AR-SV) 的新型降解剂
  • 批准号:
    10341060
  • 财政年份:
    2019
  • 资助金额:
    $ 39.73万
  • 项目类别:
Novel Degraders of the Androgen Receptor (AR) and AR Splice Variants (AR-SVs)
雄激素受体 (AR) 和 AR 剪接变体 (AR-SV) 的新型降解剂
  • 批准号:
    10524244
  • 财政年份:
    2019
  • 资助金额:
    $ 39.73万
  • 项目类别:
Discovery and Development of Selective Androgen Receptor Irreversible Covalent Antagonist (SARICA)
选择性雄激素受体不可逆共价拮抗剂(SARICA)的发现和开发
  • 批准号:
    10302036
  • 财政年份:
    2019
  • 资助金额:
    $ 39.73万
  • 项目类别:

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Androgen receptor: A master regulator of lipid metabolism
雄激素受体:脂质代谢的主要调节因子
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Role of the Androgen Receptor in Insulin Secretion in the Male
雄激素受体在男性胰岛素分泌中的作用
  • 批准号:
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ONCT-505(一种雄激素受体拮抗剂和降解剂)的临床前开发,作为肯尼迪病的新潜在治疗方法
  • 批准号:
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Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation
气道炎症期间雄激素受体 (AR) 信号对 CD4 T 细胞代谢的影响
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TITLE: BLADDER CANCER CHEMOPREVENTION USING THE ANDROGEN RECEPTOR INHIBITOR APALUTAMIDE
标题:使用雄激素受体抑制剂阿帕鲁胺进行膀胱癌化学预防
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