Novel approaches to targeted protein degradation

“特异性蛋白质降解剂在临床上用于治疗乳腺癌和前列腺癌，例如特异性雌激素受体降解剂（SERD）。我们将使用这些配体设计基于已知的雌激素受体（ER）降解配体的原型degron，并为所选的POI配体提供合适的连接体。将在适当的细胞系中测量这些降解剂对POI的降解能力。内质网降解的治疗相关性已得到充分证实；然而，阻力是一个常见的问题。双降解提供了靶向激素反应性肿瘤的机会，特异性敲除另一个相关的治疗靶点。除了serd的研究，我们还将研究其他在癌症中过度表达的不稳定蛋白。例如，母胚胎亮氨酸拉链激酶（MELK）被siRNA研究鉴定为癌症的治疗靶点。大量的制药投资用于鉴定有效的小分子抑制剂，这些抑制剂随后进入临床试验。然而，尽管MELK在乳腺癌中升高，但MELK的抑制和降解没有后果。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。我们将设计与蛋白质配体（POI）连接的癌蛋白靶向降解子，这些蛋白质配体对细胞存活和进展至关重要，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探索。靶向蛋白降解是药物发现、化学和生物学领域的一个“热门话题”。这个项目为蛋白质降解提供了一种新的方法，并将提供很好的培训。”

"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."