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

项目摘要 针对全长雄激素受体(AR)C末端配体结合域的新疗法 阿比特龙和苯扎鲁胺等LBD为晚期前列腺癌患者提供生存益处 癌症。不幸的是，这些疗法并不能治愈。对这些疗法产生抵抗的一个主要机制是 缺失LBD的截短的结构性活性AR剪接变异体(AR-vs)的表达。前列腺癌 转移灶表达AR-V的患者应该接受替代治疗(例如紫杉烷)。 而不是FL-AR的抑制剂。不幸的是，到目前为止还没有可用的技术来区分 转移灶表达AR-VS。循环中的肿瘤细胞有许多局限性，不能提供 有关个别病变的信息，例如特定病变是否对治疗有反应，而其他 病变可能对治疗难以奏效。 N-末端结构域(NTD)是FL-AR和AR-V共同的结构域，对它们的转录是必不可少的 推动前列腺癌增长的活动。因此，先天性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，如EPI和辛托卡胺 (Sint/LPY)已被证明能直接与AR-NTD结合并阻断FL-NTD的转录活性。 AR和AR-V。这些化合物在抗去势前列腺癌临床前模型中的作用 (CRPC)导致了EPI化合物的临床发展。EPI-506展示了第一个概念验证- 阿比特龙治疗失败的重度CRPC患者的人类剂量递增I期临床试验 和/或苯扎鲁胺，从而支持靶向AR-NTD和EPI支架的方法。这是 第一次，任何直接结合到内在紊乱区域的药物都进入了临床试验。 在这里，我们聚集了顶尖的专家来开发下一代药物，这种药物可以结合到本质上的无序 Ar-NTD作为CRPC的显像剂和治疗方法对预后和治疗的影响。我们的短期目标是 评估EPI-002(雷拉尼汀)和Sint/LPY的第二代类似物，其性能最高可提高125倍 效力与第一代化合物相比。这在目标1和目标2中得到了解决，我们将 合成具有EPI或SINT/LYP支架的AR-NTD新型粘结剂，并对其进行表征 这些化合物选择最好的候选化合物进行结构分析(目标3)，并在目标4中进行成像和 功效研究。揭示结构性变化将有助于针对这一目标开发更好的药物。 分子显像剂的创建可能会对选定的患者产生近期的临床影响 根据AR-vs在转移灶中的表达进行治疗。开发针对AR-NTD的药物以 抑制FL-AR和AR-VS将为这些患者提供一种新的治疗选择。

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.