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

• 批准号: 10296559
• 负责人: MARIANNE D SADAR
• 金额: $ 44.27万
• 依托单位: PROVINCIAL HEALTH SERVICES AUTHORITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10296559
• 关键词: Address; Androgen Antagonists; Androgen Receptor; Binding; Biological Assay; Biological Markers; C-terminal; Cancer Patient; Castration; Clinical; Clinical Management; Clinical Research; Clinical Trials; Complex; Cryoelectron Microscopy; Data; Development; Disease; Dissociation; Dose; Drug Targeting; Future; Gene Expression; Generations; Genetic Transcription; Goals; Growth; Hormonal; Image; Immunoprecipitation; Individual; Length; Lesion; Ligand Binding Domain; Ligation; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Mediating; Methods; Monitor; N-terminal; Neoplasm Circulating Cells; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Positioning Attribute; Pre-Clinical Model; Prognosis; Property; Proteins; RNA Splicing; Receptor Activation; Receptor Signaling; Refractory; Resistance; Resolution; Roentgen Rays; Sampling; Specificity; Stanolone; Structure; Technology; Testing; Therapeutic; Time; Variant; X-Ray Crystallography; abiraterone; advanced prostate cancer; alternative treatment; analog; base; castration resistant prostate cancer; clinical development; design and construction; drug development; efficacy study; first-in-human; hormone therapy; imaging agent; imaging approach; imaging study; improved; in vivo; inhibitor/antagonist; insight; light scattering; molecular imaging; new therapeutic target; next generation; novel; novel therapeutics; particle; pharmacodynamic biomarker; prevent; protein protein interaction; resistance mechanism; response; scaffold; small molecule; taxane; therapy resistant; transcription factor; transcriptome sequencing; treatment choice; treatment response; uptake; whole body imaging

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.

项目摘要 针对全长（FL）雄激素受体（AR）C末端配体结合域的新疗法 (LBD)如阿比特龙和恩杂鲁胺为晚期前列腺患者提供了生存益处 癌不幸的是，这些疗法并不能治愈。对这些疗法产生耐药性的主要机制是 缺乏LBD的截短的组成型活性AR剪接变体（AR-Vs）的表达。前列腺癌 应向具有表达AR-V的转移性病变的患者提供替代治疗（例如，紫杉烷） 而不是FL-AR的抑制剂。不幸的是，到目前为止，还没有技术可以区分 转移性病变表达AR-Vs。循环肿瘤细胞有许多局限性， 关于个体病变的信息，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。 病变可能是治疗难治的。 N-末端结构域（NTD）是FL-AR和AR-V共有的，并且对于它们的转录调控是必需的。 前列腺癌的症状有哪些？因此，本征无序的AR-NTD是一种新的治疗药物 药物开发的目标。我们已经发现了所有的小分子，如EPI和Sintokamide (SINT/LPY），其已被证明直接结合AR-NTD并阻断FL-1的转录活性。 AR和AR-Vs.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EPI化合物的临床开发。EPI-506在首次 在阿比特龙治疗失败的重度预治疗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 这是第一次有任何药物直接结合到一个内在无序的区域进入临床试验。 在这里，我们聚集了领先的专家，以开发下一代药物， AR-NTD作为CRPC预后和治疗的显像剂和治疗剂。我们的短期目标是 评价EPI-002（雷拉尼丁）和SINT/LPY的第二代类似物， 与第一代化合物相比，这在目标1和2中得到了解决，我们将 合成具有EPI或SINT/LYP支架的AR-NTD的新型结合剂，然后将表征 这些化合物，以选择最佳候选人的结构分析（目标3），并在目标4成像和 功效研究。揭示结构变化将有助于开发针对这一目标的更好药物。 分子成像剂的创建可能会为选择的患者提供近期临床影响 基于AR-V在转移性病变中的表达的治疗。开发针对AR-NTD的药物， 抑制FL-AR和AR-V将为这些患者提供新治疗选择。