Investigating Novel Functions of DCAF16 and unveiling its Degron Sequence for the development of novel drugs (DEGRON)

Targeted therapies are designed to attack specific molecules that are involved in cancer growth and spread. In recent years, targeted therapies have made significant progress in treating cancer and have become a powerful option for cancer patients. Molecular Glues (MGs) have caught the attention of the scientific community due to their ability to induce the degradation of target proteins related to diseases previously considered "undruggable". MGs have been described to enhance and stabilize existing protein-protein interactions within the cell. This stabilization often results in proteins being tagged with ubiquitin, marking them for destruction by the cell's own recycling machinery, the proteasome. Unfortunately, as these molecules have predominantly been serendipitously discovered, there is a lack of rationality behind de novo MG design. Consequently, this pharmacological modality has thus far been unable to reach its full potential. Funded by the UKRI Postdoctoral Fellowships Guarantee scheme, the DEGRON project aims to establish the first guidelines of MG "rational design" enabling the development of more diverse and more potent MGs. The project will achieve this by expanding the understanding of DCAF16, a promising E3 Ligase recently reported to be recruited by MGs, at a functional, structural, and biophysical level. Unveiling the mode of action of DCAF16 and its interacting proteins will spark further research into the development of novel MGs against disease-linked proteins, driving medical intervention. Undoubtedly, establishing guidelines for developing DCAF16-based rationally designed MGs may inspire similar work with other E3 ligases, yielding potent and innovative drugs. This could reshape oncology treatment throughout Europe by expanding the number of proteins to be targeted, amplifying therapeutic benefits for patients.