Targeted Protein Degradation using Small Molecules

The existing paradigm for small molecule drug therapy involves interactions of drugs with their protein targets. A necessary implication of this approach is that any individual drug molecule can only affect a single target site at any given time. An emerging medicinal chemistry strategy seeks to overturn the inherent 1:1 requirement for drug:target interactions through selectively induced protein degradation. This is achieved using bifunctional molecules known as Protacs (for Proteolysis Targeting Chimeras). Crucially, the small molecule Protac itself is not degraded in this process, as it is not recognized by the proteasome. This means that a single Protac is able to induce the degradation of many copies of its protein target, a type of catalytic activity that is simply not possible with standard small molecules. This catalytic nature opens the possibility for much lower dosing without compromising efficacy. The relatively recent development of Protac technology means that this technique has not yet been widely explored. This studentship will explore protein degradation in new contexts of direct relevance to human disease. The project is therefore perfectly aligned with the EPSRC's Chemical Biology research area, which has been targeted for Growth.