Single-domain antibody, proteolysis-targeting chimera constructs (sdAb-PROTAC) for the specific intra-cellular degradation of protein targets

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Many dysregulated proteins in cancers, ones which are over-expressed and/ or mutated, can be classified as 'undruggable', meaning they do not have enzymatic function or any obviously amenable binding site to design a small-molecule inhibitor for. Proteolysis-targeting chimera molecules (PROTACs) are bifunctional molecules that induce proximity between a protein target and an E3 ligase, which initiates polyubiquitination of the protein target leading to proteosomal degredation. The aim of this project is to utilise the selectivity and stability of single-domain antibodies (sdAbs) to produce PROTAC conjugates capable of intracellular protein degredation of previously 'undruggable' targets.