Structural and functional analysis of a novel class of androgen receptor antagonists

一类新型雄激素受体拮抗剂的结构和功能分析

基本信息

批准号：
10650956
负责人：
Zhou Wang
金额：
$ 14.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650956
关键词：
American Androgen Antagonists Androgen Receptor Androgen Response Element Androgens Binding Biological Assay Cancer Etiology Cancer Patient Castration Cell Nucleus Cells Cessation of life Chemicals Complex Cryoelectron Microscopy DU145 Data Development FDA approved Generations Genes Goals In Vitro Lead Length Libraries Ligand Binding Domain Malignant neoplasm of prostate Medicine Metastatic Prostate Cancer Methodology Methods Modeling Nuclear PC3 cell line Parents Patients Proliferating Prostate Cancer therapy RNA Splicing Receptor Activation Relapse Resistance Resistance development Ru-1881 Solubility Specificity Stanolone Structure-Activity Relationship Surface Plasmon Resonance Testing Universities Variant abiraterone analog androgen deprivation therapy antagonist aqueous castration resistant prostate cancer chromatin immunoprecipitation course development design detection assay dosage driving force drug development enzalutamide improved inhibitor mRNA Expression men next generation novel novel strategies novel therapeutics particle prostate cancer cell prostate cancer cell line receptor binding scaffold small molecule success targeted agent targeted treatment tumor growth tumor xenograft

项目摘要

Project Summary Title: Structural and functional analysis of a novel class of androgen receptor antagonists Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeting agents are the mainstay of metastatic prostate cancer (PCa) treatment. However, PCa on ADT and/or AR-targeting agents usually lead to relapse and castration-resistant prostate cancer (CRPC), which is mainly driven by AR activation under castration conditions. Next-generation AR-targeting agents such as enzalutamide and abiraterone can inhibit AR in CRPC but prolong the survival of CRPC patients for only about 4-5 months on average. The major mechanism responsible for the resistance to next-generation AR-targeting agents is reactivation of AR. Novel strategies to block the development of resistance to the current AR-targeted therapy are an urgent need and a major drug development challenge. Existing FDA-approved AR antagonists compete with dihydrotestosterone (DHT) for binding to the ligand binding domain (LBD) of AR, and patients eventually develop resistance to these treatments. One approach to overcoming resistance is to develop compounds that inhibit AR in alternative ways. We have identified a small molecule, SID 3712502, that is capable of inhibiting AR lacking LBD. To optimize the efficacy of this new class of inhibitors, we developed structural analogues and identified (+)-JJ-74-138 as a promising candidate. Our preliminary data suggest that (+)-JJ-74-138 is a novel AR antagonist capable of degrading nuclear AR and inhibiting enzalutamide-resistant CRPC both in culture and in xenograft tumors. However, it is not yet clear how AR interacts with (+)-JJ-74-138, which makes it difficult to rationally develop more potent analogues. We propose the following 2 specific aims to define how (+)-JJ-74- 138 and its parent compound SID 3712502 bind to AR and develop new analogs with improved potency, aqueous solubility and specificity for inhibition and degradation of nuclear AR. Aim 1 will determine how the SID 3712502 scaffold binds to AR using cryogenic electron microscopy (cryoEM). We will purify full-length AR (AR-FL), characterize interactions of AR-FL with SID 3712502 and (+)-JJ-74-138 for cryoEM structural analysis of a suitable complex of AR-FL2/R1881/ARE/SID 3712502 (or (+)-JJ-74-138) using single particle methods. Aim 2 will design, synthesize and analyze analogues of (+)-JJ-74-138, with the goal to identify small molecules with submicromolar potency, improved aqueous solubility, and high specificity for AR-positive cells. We will systematically prepare analogs of the lead compound(s) in iterative rounds of physicochemical improvements and optimizations based on structure–activity relationship (SAR) analyses from in vitro and cell-based assays. The success of this project will greatly facilitate the development of this class of novel AR antagonists for the treatment of CRPC, including enzalutamide-resistant CRPC.

项目概要标题：一类新型雄激素受体拮抗剂的结构和功能分析雄激素剥夺疗法（ADT）和雄激素受体（AR）靶向药物是主要的治疗方法然而，PCa 的 ADT 和/或 AR 靶向药物通常会导致转移性前列腺癌 (PCa) 治疗。复发和去势抵抗性前列腺癌（CRPC），主要是由 AR 激活驱动的下一代 AR 靶向药物，如恩杂鲁胺和阿比特龙可以抑制。 AR在CRPC中发挥作用，但只能延长CRPC患者的平均生存期约4-5个月。导致对下一代 AR 靶向药物产生耐药性的机制是 AR 的重新激活。迫切需要采取策略来阻止对当前 AR 靶向治疗产生耐药性 FDA 批准的现有 AR 拮抗剂与二氢睾酮竞争是药物开发的主要挑战。 (DHT) 与 AR 的配体结合域 (LBD) 结合，患者最终产生耐药性克服耐药性的一种方法是开发抑制 AR 的化合物。我们已经鉴定出一种小分子 SID 3712502，它能够抑制 AR 缺乏。为了优化这类新型抑制剂的功效，我们开发了结构类似物并进行了鉴定。 (+)-JJ-74-138 作为一个有前途的候选者，我们的初步数据表明 (+)-JJ-74-138 是一种新型 AR。能够降解核 AR 并抑制恩杂鲁胺抗性 CRPC 的拮抗剂，无论是在培养物还是在然而，目前尚不清楚 AR 如何与 (+)-JJ-74-138 相互作用，这使得很难我们提出以下 2 个具体目标来定义 (+)-JJ-74-。 138 及其母体化合物 SID 3712502 与 AR 结合并开发具有改进效力的新类似物，水溶性和抑制和降解核 AR 的特异性将决定如何。 SID 3712502 支架使用低温电子显微镜 (cryoEM) 与 AR 结合，我们将纯化全长 AR。 (AR-FL)，表征 AR-FL 与 SID 3712502 和 (+)-JJ-74-138 的相互作用，用于冷冻电镜结构分析使用单颗粒方法制备合适的 AR-FL2/R1881/ARE/SID 3712502（或 (+)-JJ-74-138）复合物。目标2将设计、合成和分析(+)-JJ-74-138的类似物，目标是识别小分子具有亚微摩尔效力、改善的水溶性以及对 AR 阳性细胞的高特异性。在物理化学改进的迭代过程中系统地制备先导化合物的类似物以及基于体外和细胞测定的构效关系（SAR）分析的优化。该项目的成功将极大地促进此类新型AR拮抗剂的开发 CRPC 的治疗，包括恩杂鲁胺耐药的 CRPC。