Novel approaches to targeted protein degradation

点击翻译按钮获取中文摘要

"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."