Small molecule-induced protein degradation for the prevention of metastasis

Dr David France (Chemistry, University of Glasgow)
Dr Justin Bower (Drug Discovery, CRUK Beatson Institute)
Prof Laura Machesky (CRUK Beatson Institute)

The standard model for drug therapy relies on a 1:1 correlation between a drug molecule and its biomolecular target. Drug dosing regimens must take this requirement into account. This is a particular challenge for cancer therapy where distinguishing between cancer cells and healthy cells is essential to avoid toxic side effects. An emerging strategy in Medicinal Chemistry called “Protac” attempts to overcome the requirement for a 1:1 correspondence between drugs and their targets. This is achieved through the selective degradation of multiple copies of a target protein by a single Protac molecule. The consequent ability to use low drug doses has the potential to lead to new cancer therapies with minimal toxic side effects. This project will examine the Protac approach in the context of the actin bundling protein Fascin. Fascin is a uniquely good therapeutic target because it is not expressed in most normal epithelial tissues, but is strongly upregulated during multiple tumour progression programmes, including in pancreatic cancer, breast cancer and colorectal cancers. The student will work with experts in multiple disciplines including chemical synthesis of the Protac molecules, structural biology to design compounds with optimized binding, and cellular invasion assays to determine efficacy. Ultimately, this project aims to validate the Protac approach to preventing cancer invasion and metastasis by degradation of Fascin.

Keywords: Protac, Protein degradation, Cell migration and invasion, Cancer metastasis, Pancreatic cancer


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