Structure, function, and application of novel antagonists of the intrinsically disordered androgen receptor amino-terminal domain as imaging agents and therapeutics

本质紊乱的雄激素受体氨基末端结构域的新型拮抗剂的结构、功能和作为显像剂和治疗剂的应用

基本信息

批准号：
10670364
负责人：
MARIANNE D SADAR
金额：
$ 43.7万
依托单位：
PROVINCIAL HEALTH SERVICES AUTHORITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-13 至 2026-06-30
项目状态：
未结题

项目摘要

Project Summary Newer therapies directed at the full-length (FL) androgen receptor (AR) C-terminal ligand-binding domain (LBD) such as abiraterone and enzalutamide provide survival benefits to patients with advanced prostate cancer. Unfortunately, these therapies are not curative. A major mechanism of resistance to these therapies is the expression of truncated constitutively active AR splice variants (AR-Vs) that lack the LBD. Prostate cancer patients with metastatic lesions that express AR-Vs should be offered alternative treatments (e.g., taxanes) instead of inhibitors of FL-AR. Unfortunately, to date there is no technology available that can distinguish which metastatic lesions express AR-Vs. Circulating tumor cells have many limitations and cannot provide information about the individual lesions such as whether a specific lesion is responding to therapy while other lesions may be refractory to the treatment. The N-terminal domain (NTD) is common to both FL-AR and AR-Vs and is essential for their transcriptional activities to drive prostate cancer growth. Therefore the intrinsically disordered AR-NTD is a novel therapeutic target for drug development. We have discovered all of the small molecules such as EPI and sintokamide (SINT/LPY) that have been proven to directly bind to the AR-NTD and block the transcriptional activities of FL- AR and AR-Vs. Efficacy of these compounds in preclinical models of castration resistance prostate cancer (CRPC) led to the clinical development of EPI compounds. EPI-506 showed proof-of-concept in a first-in- human dose escalation Phase I clinical trial in heavily pre-treated CRPC patients that had failed abiraterone and/or enzalutamide thereby supporting the approach of targeting the AR-NTD and the EPI scaffold. This was the first time any drug that directly binds to an intrinsically disordered region reached clinical trials. Here we assemble leading experts to develop next generation drugs that bind to the intrinsically disordered AR-NTD as imaging agents and therapeutics for the prognosis and treatment of CRPC. Our short term goal is to evaluate second generation analogues of EPI-002 (ralaniten) and SINT/LPY that have up to 125-fold better potency compared to the first generation compounds. This is addressed in Aims 1 and 2 where we will synthesize novel binders of AR-NTD that have either the EPI or SINT/LYP scaffold and then will characterize these compounds to select the best candidates for structural analyses (Aim 3), and in Aim 4 for imaging and efficacy studies. Revealing structural changes will aid in the development of better drugs against this target. Creation of a molecular imaging agent would potentially provide near-term clinical impact to select patient treatments based upon expression of AR-Vs in metastatic lesions. Developing drugs that target the AR-NTD to inhibit both FL-AR and AR-Vs would provide a novel treatment option for these patients.

项目概要针对全长 (FL) 雄激素受体 (AR) C 端配体结合域的新型疗法 (LBD)，如阿比特龙和恩杂鲁胺为晚期前列腺患者提供生存益处癌症。不幸的是，这些疗法并不能治愈。对这些疗法产生耐药性的一个主要机制是缺乏 LBD 的截短的组成型活性 AR 剪接变体 (AR-V) 的表达。前列腺癌应为患有表达 AR-V 的转移性病变的患者提供替代治疗（例如紫杉烷类药物）代替 FL-AR 抑制剂。不幸的是，迄今为止还没有可用的技术可以区分哪些转移灶表达 AR-V。循环肿瘤细胞有很多局限性，不能提供有关各个病变的信息，例如特定病变是否对治疗有反应，而其他病变是否对治疗有反应病变可能难以治疗。 N 端结构域 (NTD) 是 FL-AR 和 AR-V 所共有的，对于它们的转录至关重要促进前列腺癌生长的活动。因此，本质上紊乱的 AR-NTD 是一种新的治疗方法药物开发的目标。我们已经发现了所有的小分子，例如EPI和sintokamide (SINT/LPY) 已被证明可直接结合 AR-NTD 并阻断 FL- 的转录活性 AR 和 AR-V。这些化合物在去势抵抗性前列腺癌临床前模型中的功效 (CRPC) 导致了 EPI 化合物的临床开发。 EPI-506 在首创中展示了概念验证在阿比特龙治疗失败的经过大量治疗的 CRPC 患者中进行的人体剂量递增 I 期临床试验和/或恩杂鲁胺，从而支持靶向 AR-NTD 和 EPI 支架的方法。这是这是第一次任何直接与内在紊乱区域结合的药物进入临床试验。在这里，我们聚集了领先的专家来开发下一代药物，与本质上无序的疾病结合 AR-NTD 作为显像剂和治疗剂用于 CRPC 的预后和治疗。我们的短期目标是评估 EPI-002 (ralaniten) 和 SINT/LPY 的第二代类似物，其性能提高了 125 倍与第一代化合物相比的效力。这在目标 1 和 2 中得到解决，我们将合成具有 EPI 或 SINT/LYP 支架的 AR-NTD 新型结合物，然后表征这些化合物来选择结构分析的最佳候选化合物（目标 3），以及目标 4 的成像和功效研究。揭示结构变化将有助于针对这一目标开发更好的药物。分子成像剂的创建可能会给选定的患者带来近期临床影响基于转移性病灶中 AR-V 表达的治疗。开发针对 AR-NTD 的药物抑制 FL-AR 和 AR-V 将为这些患者提供一种新的治疗选择。