Novel approaches to targeted protein degradation

特定的蛋白质降解物被用于临床治疗乳腺癌和前列腺癌，例如特定的雌激素受体降解物(SERD)。我们将使用这些配体在已知的雌激素受体(ER)降解配体的基础上设计原型降解物，并将适当的连接物连接到选定POI的配体。降解物影响POI降解的能力将在适当的细胞系中进行测量。内质网降解的治疗相关性已经确立；然而，耐药性是一个经常出现的问题。双重降解物提供了通过特定敲除另一个相关治疗靶点来靶向激素反应肿瘤的机会。除了对SERDS的研究外，我们还将研究在癌症中过度表达的其他不稳定蛋白质。例如，母体胚胎亮氨酸拉链酶(Melk)被siRNA研究确定为癌症的治疗靶点。进行了大量的药物投资，以确定有效的小分子抑制剂，并随后投入临床试验。然而，尽管乳腺癌中的Melk升高，但对Melk的抑制和降解没有影响。MELK1在发现的配体存在的情况下被降解，因此为癌基因靶向降解提供了机会。我们将设计与蛋白质配体(POI)相连的癌蛋白靶向性退化蛋白，这些蛋白对细胞的生存和发展至关重要，或者降解可能引发细胞凋亡。这些分子在表达癌蛋白的细胞系中的细胞活性将被发掘。靶向蛋白降解是药物发现、化学和生物学中的一个热门话题。这个项目提供了一种新的蛋白质降解方法，并将提供极好的培训。“

"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."