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:
- 金额:$ 36.7万
- 依托单位:
- 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:
- 关键词:AmericanAndrogen AntagonistsAndrogen ReceptorAndrogensBindingBinding ProteinsBiological AssayCancer EtiologyCastrate sensitive prostate cancerCastrationCell NucleusCessation of lifeCo-ImmunoprecipitationsCoupledDataDevelopmentDrug KineticsFractionationGenerationsGoalsImportinsLeadMalignant neoplasm of prostateMediatingMicrosomesModelingNuclearNuclear ImportNuclear ReceptorsPatientsPharmaceutical ChemistryPlasma ProteinsProstate Cancer therapyResistanceSmall Interfering RNASpecificityTestingTherapeuticTherapeutic AgentsUbiquitinationWorkXenograft procedureanalogcancer diagnosiscastration resistant prostate cancerdriving forceeffective therapyefficacy evaluationenzalutamidehigh throughput screeningimprovedin vivoknock-downmennovelnovel strategiesoverexpressionpatient populationpreventprostate cancer cellprostate cancer preventionprostate cancer progressionreceptor expressionscreeningsmall moleculesuccesssynergismtargeted agenttherapeutic targettooltranscription factortumortumor growthtumor xenograftubiquitin-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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mechanisms and targeting of proteosome-dependent androgen receptor degradation in prostate cancer.
前列腺癌中蛋白酶体依赖性雄激素受体降解的机制和靶向。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:1.2
- 作者:Fang,Qinghua;Cole,RyanN;Wang,Zhou
- 通讯作者:Wang,Zhou
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Zhou Wang的其他文献
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{{ truncateString('Zhou Wang', 18)}}的其他基金
Structural and functional analysis of a novel class of androgen receptor antagonists
一类新型雄激素受体拮抗剂的结构和功能分析
- 批准号:
10650956 - 财政年份:2023
- 资助金额:
$ 36.7万 - 项目类别:
Role of E-Cadherin Down-Regulation in Prostatic Inflammation and Lower Urinary Tract Dysfunction
E-钙粘蛋白下调在前列腺炎症和下尿路功能障碍中的作用
- 批准号:
10564514 - 财政年份:2023
- 资助金额:
$ 36.7万 - 项目类别:
University of Pittsburgh O'Brien Cooperative Research Center Program
匹兹堡大学奥布莱恩合作研究中心项目
- 批准号:
9230541 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
University of Pittsburgh O'Brien Cooperative Research Center Program
匹兹堡大学奥布莱恩合作研究中心项目
- 批准号:
10002325 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
The University of Pittsburgh O'Brien Urology Cooperative Research Center Program
匹兹堡大学奥布莱恩泌尿科合作研究中心项目
- 批准号:
10002341 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
University of Pittsburgh O'Brien Cooperative Research Center Program
匹兹堡大学奥布莱恩合作研究中心项目
- 批准号:
9764149 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
Luminal epithelial junctions, polarity, and permeability in BPH pathogenesis
BPH 发病机制中的管腔上皮连接、极性和渗透性
- 批准号:
10002344 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
University of Pittsburgh O'Brien Cooperative Research Center Program
匹兹堡大学奥布莱恩合作研究中心项目
- 批准号:
9357574 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
Luminal Epithelial Junctions, Polarity, and Permeability in BPH Pathogenesis
BPH 发病机制中的管腔上皮连接、极性和渗透性
- 批准号:
9323061 - 财政年份:2016
- 资助金额:
$ 36.7万 - 项目类别:
Molecular signatures associated with prostatic inflammation in rodent models.
啮齿动物模型中与前列腺炎症相关的分子特征。
- 批准号:
8566145 - 财政年份:2012
- 资助金额:
$ 36.7万 - 项目类别:














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