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Targeting androgen receptor nuclear localization in prostate cancer

前列腺癌中雄激素受体核定位的靶向

基本信息

批准号：
10642683
负责人：
Zhou Wang
金额：
$ 36.7万
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：
2022
资助国家：
美国
起止时间：
2022-06-10 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10642683
关键词：
American Androgen Antagonists Androgen Receptor Androgens Binding Binding Proteins Biological Assay Cancer Etiology Castrate sensitive prostate cancer Castration Cell Nucleus Cessation of life Co-Immunoprecipitations Coupled Data Development Drug Kinetics Fractionation Generations Goals Importins Lead Malignant neoplasm of prostate Mediating Microsomes Modeling Nuclear Nuclear Import Nuclear Receptors Patients Pharmaceutical Chemistry Plasma Proteins Prostate Cancer therapy Resistance Small Interfering RNA Specificity Testing Therapeutic Therapeutic Agents Ubiquitination Work Xenograft procedure analog cancer diagnosis castration resistant prostate cancer driving force effective therapy efficacy evaluation enzalutamide high throughput screening improved in vivo knock-down men novel novel strategies overexpression patient population prevent prostate cancer cell prostate cancer prevention prostate cancer progression receptor expression screening small molecule success synergism targeted agent therapeutic target tool transcription factor tumor tumor growth tumor xenograft ubiquitin-protein ligase

项目摘要

Project Summary Title: Targeting androgen receptor nuclear localization in prostate cancer Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer death in American men. More effective therapies for PCa are urgently needed. The androgen receptor (AR) is a key therapeutic target for PCa. AR appears to be overexpressed, stabilized, and nuclear-localized in castration- resistant PCa (CRPC). AR nuclear localization is necessary for its function as a transcription factor. We have developed a high-throughput screen and identified two closely related pyrroloimidazoles, CPPI and EPPI, which can inhibit AR nuclear localization in CRPC. These small molecules inhibited all tested AR-positive prostate cancer cells, including enzalutamide-resistant CRPC. Further studies suggested that these small molecules can directly bind to AR and enhance AR ubiquitination and degradation in the nucleus, acting as nuclear AR degraders (NARDs). Since CRPC is associated with increased AR level and stability, inhibition or even partial inhibition of AR level may slow down the progression to CRPC. Here, we hypothesize that NARD can inhibit CRPC and prostate cancer progression to castration resistance. Also, NARD may enhance the efficacy of other AR targeting agents because resistance to AR targeting agents is also associated with increased AR expression. To explore the therapeutic potential of NARD, 3 specific aims are proposed. Aim 1 will determine the mechanisms by which CPPI inhibits AR nuclear localization in CRPC cells. Aim 2 will evaluate potential synergies of CPPI with other AR-targeting approaches. Aim 3 will synthesize and characterize novel analogues of CPPI with the goal to identify new lead NARD compounds with submicromolar potency and high specificity for AR-positive PCa cells. Success of the proposed project may lead a strategy to slow down the progression of prostate cancer to castration resistance and to an alternative approach to PROTAC AR degraders, which are being actively investigated as a therapeutic agent for AR-positive CRPC. Since the mechanisms of NARD action are different from PROTAC-type AR degraders, NARD may be more suitable than PROTAC AR degraders in certain patient populations.

项目概要标题：靶向前列腺癌中的雄激素受体核定位前列腺癌 (PCa) 是最常诊断的癌症，也是癌症死亡的第二大原因美国男人。迫切需要更有效的前列腺癌治疗方法。雄激素受体（AR）是关键 PCa 的治疗靶点。 AR 似乎在去势过程中过度表达、稳定且定位于核- 耐药 PCa (CRPC)。 AR 核定位对于其作为转录因子的功能是必要的。我们有开发了高通量筛选并鉴定了两种密切相关的吡咯并咪唑，CPPI 和 EPPI，它可以抑制CRPC中的AR核定位。这些小分子抑制了所有测试的 AR 阳性前列腺癌细胞，包括恩杂鲁胺耐药的 CRPC。进一步的研究表明，这些小分子可以直接与AR结合并增强AR在细胞核中的泛素化和降解，起到核 AR 降解剂 (NARD)。由于 CRPC 与 AR 水平和稳定性增加有关，因此抑制或即使部分抑制 AR 水平也可能减缓 CRPC 的进展。在这里，我们假设 NARD 可以抑制 CRPC 和前列腺癌进展为去势抵抗。此外，NARD 可能会增强其他 AR 靶向剂的功效，因为对 AR 靶向剂的耐药性也与 AR表达增加。为了探索 NARD 的治疗潜力，提出了 3 个具体目标。目标1 将确定 CPPI 抑制 CRPC 细胞中 AR 核定位的机制。目标2将评估 CPPI 与其他 AR 靶向方法的潜在协同作用。目标 3 将综合并表征 CPPI 的新型类似物，目标是识别具有亚微摩尔浓度的新型先导 NARD 化合物对 AR 阳性 PCa 细胞具有效力和高特异性。拟议项目的成功可能会导致一项战略减缓前列腺癌向去势抵抗的进展，并提供替代方法 PROTAC AR 降解剂，正在积极研究其作为 AR 阳性 CRPC 的治疗剂。由于 NARD 的作用机制与 PROTAC 型 AR 降解剂不同，NARD 可能更比 PROTAC AR 降解剂更适合某些患者群体。