Development of DNA-PK-targeting PROTACs to maximise DNA-PK blockage in advanced prostate cancer

开发 DNA-PK 靶向 PROTAC 以最大限度地阻断晚期前列腺癌的 DNA-PK

• 批准号: 2877287
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2877287
• 关键词: Development; DNA; PK; targeting; PROTACs

Prostate cancer accounts for 375,000 deaths per year worldwide. Targeting the androgen receptor (AR) using hormone therapy is the mainstay treatment for advanced prostate cancer. Unfortunately, not all patients show durable responses; with many becoming resistant to radiotherapy or acquiring mechanisms that overcome AR blockade. Hence, there is an urgent need to provide more effective and durable treatments for metastatic disease. In advanced prostate cancer, DNA-dependent protein kinase (DNA-PK) expression is elevated and correlates with metastatic spread. The project has two main objectives: 1) to develop DNA-PKcs PROTACs to destabilise DNA-PKcs in prostate cancer; 2) to demonstrate unequivocal levels of DNA-PKcs inhibition in a range of in vitro assays across a range of prostate cancer cell lines and provide the means to evaluate DNA-PK degradation as a potential treatment in advanced prostate cancer.

全世界每年有375,000人死于前列腺癌。以雄激素受体(AR)为靶点的激素治疗是晚期前列腺癌的主要治疗方法。不幸的是，并不是所有的患者都表现出持久的反应；许多人对放射治疗产生抗药性，或者获得了克服AR阻断的机制。因此，迫切需要为转移性疾病提供更有效和更持久的治疗。在晚期前列腺癌中，DNA依赖蛋白激酶(DNA-PK)的表达升高，并与转移转移相关。该项目有两个主要目标：1)开发DNA-PKcs PROTAC来破坏前列腺癌中DNA-PKcs的稳定性；2)在一系列前列腺癌细胞系的体外实验中证明DNA-PKcs抑制的明确水平，并提供评估DNA-PK降解作为晚期前列腺癌治疗的潜在方法的手段。