Novel approaches to targeted protein degradation

靶向蛋白质降解的新方法

• 批准号: 2599260
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2599260
• 关键词: Novel; approaches; targeted; protein; degradation

"Specific protein degraders are used clinically to treat breast and prostate cancer, e.g. the specific estrogen receptor degrader (SERD). We will use these ligands to design prototype degrons based on known degrading ligands for the estrogen receptor (ER) with appropriate linkers to ligands for the chosen POI. The ability of the degrons to effect degradation of the POI will be measured in appropriate cell lines. The therapeutic relevance of ER degradation is well established; however, resistance is a frequent problem. Dual degraders offer the opportunity of targeting hormone responsive tumours with the specific knockdown of another relevant therapeutic target.In addition to studies with SERDs, we will investigate other unstable proteins that are found to be overexpressed in cancer. For example, Maternal Embryonic Leucine Zipper Kinase (MELK) was identified by siRNA studies as a therapeutic target in cancer. Large pharmaceutical investment was made identifying potent small molecule inhibitors that were subsequently taken into clinical trials. However, despite elevated MELK in breast cancer there is no consequence to MELK inhibition and degradation. MELK1 is degraded in the presence of the ligands discovered and so offers the opportunity for oncogene targeted degradation. We will design oncoprotein targeted degrons linked to ligands for proteins (POI) that are either essential for cell survival and progression, or where degradation may trigger apoptosis. The cellular activity of of these molecules in oncoprotein expressing cell lines will be explored.Targeted protein degradation is a 'hot-topic' in drug discovery chemistry and biology. This project offers a novel approach to protein degradation and will give an excellent training."

“特定的蛋白质降解剂在临床上用于治疗乳腺癌和前列腺癌，例如特定的雌激素受体降解剂 (SERD)。我们将使用这些配体来设计基于雌激素受体 (ER) 的已知降解配体的原型降解决定子，以及与所选 POI 的配体的适当接头。将在适当的细胞中测量降解决定子影响 POI 降解的能力 线。 ER 降解的治疗相关性已得到充分证实；然而，耐药性是一个常见的问题。双重降解剂提供了通过特异性敲低另一个相关治疗靶点来靶向激素反应性肿瘤的机会。除了 SERD 的研究之外，我们还将研究在癌症中过度表达的其他不稳定蛋白。例如，母体胚胎亮氨酸拉链激酶 (MELK) 被鉴定为 siRNA 研究作为癌症的治疗靶点。进行了大量的制药投资以确定有效的小分子抑制剂，随后将其纳入临床试验。然而，尽管乳腺癌中 MELK 升高，但 MELK 抑制和降解不会产生任何后果。 MELK1 在发现的配体存在下被降解，因此为癌基因靶向降解提供了机会。我们将设计靶向癌蛋白 降解决定子与蛋白质配体 (POI) 连接，这些配体对于细胞生存和进展至关重要，或者降解可能引发细胞凋亡。将探索这些分子在癌蛋白表达细胞系中的细胞活性。靶向蛋白质降解是药物发现化学和生物学中的“热门话题”。该项目提供了一种新的蛋白质降解方法，并将提供出色的 训练。”