Towards spatially-controlled, bioorthogonal, CuAAC-mediated assembly of targeted oncoprotein degraders

I propose an ambitious multidisciplinary strategy to address the challenge of targeting KRAS-mutated cancers through the combination of a novel bioorthogonal strategy to assemble bioactive agents and ‘targeted protein degradation’ (TPD).

TPD is an innovative strategy to degrade targeted proteins by hijacking the natural Ubiquitin Proteasome System (UPS) employing heterobifunctional molecules called Proteolysis Targeting Chimeras or PROTACs. These compounds have demonstrated the ability to drive the destruction of well-known harmful proteins.

However, their therapeutic implementation has been severely limited by the large size and lipophilicity of these molecules, and by concerns of systemic toxicities.

Here, we propose these issues could be circumvented by that the use of PROTACs against KRAS that are assembled from two drug-like fragments via bioorthogonal copper-catalyzed azide alkyne cycloaddition (CuAAC) mediated by Cu nanoparticles (Cu NPs) located in the tumour anatomical area.

Furthermore, to avoid the Cu NPs loss of catalytic performance caused by their interaction with the biological milieu, we propose to protect them in sachets made out of a dialysis membrane to avoid biofouling and at the same time, facilitate the entry of precursors of bioactive PROTACs.

This highly innovative project has the potential to create far-reaching tools for cancer therapy, and in doing so, promoting European Scientific Excellence.

By completing this multidisciplinary work, the applicant will be in an excellence position for create cross-disciplinary collaborations with research groups and industry across Europe and to becoming himself as an independent researcher