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: 10445076
• 负责人: MARIANNE D SADAR
• 金额: $ 43.35万
• 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/10445076
• 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; antagonist; base; castration resistant prostate cancer; clinical development; design and construction; drug development; efficacy study; enzalutamide; first-in-human; hormone therapy; imaging agent; imaging approach; imaging study; improved; in vivo; inhibitor; 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.

项目总结