ICF: Novel small molecule inhibitors for the treatment of CCNE1-amplified cancers

ICF：用于治疗 CCNE1 扩增癌症的新型小分子抑制剂

• 批准号: MR/W029499/1
• 负责人: Steve Wedge
• 金额: $ 179.51万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW029499%2F1
• 关键词: ICF; Novel; small; molecule; inhibitors

This project aims to take important steps towards developing a drug that will target the Achilles' heel of the cancerous cells found in 1 in 5 patients diagnosed with high grade serous ovarian cancer. Patients with this form of cancer currently have a very poor prognosis, and undergo harsh chemotherapy that provides limited benefits in terms of quality or duration of life. The vulnerability of the ovarian cancer in these patients arises from the fact that these particular cancer cells have multiple copies of the gene that encodes cyclin E. This results in cyclin E protein being produced at abnormally high levels and as a consequence the cells become addicted to cyclin E for their ability to further divide and survive. Our structural studies have provided novel insights into how aberrant cyclin E signaling may be prevented with a small molecule inhibitor, which would be selectively toxic to ovarian cancers that are dependent upon this pathway for survival. The project team has extensive expertise in drug discovery and has established the experimental systems needed to develop such inhibitors, with chemical start points being identified. The team has also formed collaborations with clinical experts who specialise in the treatment of aggressive ovarian cancers. Clinicians would be able to easily identify the patients with elevated cyclin E who would benefit from a drug developed for these tumour cells; an example of a personalised medicine. By the end of the project, the team aims to have developed the inhibitors to a point where they can demonstrate selective effects on ovarian cancer cells with elevated cyclin E levels. This would position the project for further development involving the final optimisation of inhibitors towards a drug that could be developed for clinical use.

该项目旨在采取重要步骤开发一种药物，该药物将针对5例诊断为高级浆液卵巢癌的5例患者中有1例癌细胞的脚跟。患有这种形式的癌症的患者目前的预后较差，并且接受苛刻的化学疗法，从而在质量或生命持续时间方面提供了有限的好处。这些患者中卵巢癌的脆弱性源于以下事实：这些特定的癌细胞具有编码细胞周期蛋白的基因的多个副本。这会导致在异常高水平的细胞周期蛋白E蛋白产生的基因，因此细胞上瘾于细胞周期蛋白E的能力进一步分裂和生存。我们的结构研究为如何使用小分子抑制剂预防异常的细胞周期蛋白信号传导提供了新的见解，该抑制剂将对卵巢癌有选择性地毒性，这些卵巢癌依赖于这种生存途径。该项目团队在药物发现方面拥有广泛的专业知识，并建立了开发这种抑制剂所需的实验系统，并确定了化学起点。该团队还与专门治疗侵略性卵巢癌的临床专家建立了合作。临床医生将能够轻松地识别细胞周期蛋白E升高的患者，这些患者将从为这些肿瘤细胞开发的药物中受益；个性化药物的一个例子。到项目结束时，该团队的目标是将抑制剂开发到一个可以证明对细胞周期蛋白E水平升高的卵巢癌细胞的选择性影响。这将定位该项目进行进一步开发的项目，涉及最终优化可以用于临床使用的药物的抑制剂。