Mechanisms of protein degradation via hydrophobic tagging

In this project we want to advance the concept of targeted protein degradation (TPD). TPD is a field that aims to develop and understand small molecules that can hijack the cellular degradation machinery to induce the degradation of proteins of interests (POIs). The most relevant POIs are disease-causing but are considered as undruggable with conventional pharmacologic strategies. In other words, the traditional approaches that rely on finding competitive inhibitors are unlikely to yield medicines for these proteins. Among many reasons, it might for instance be that the POI doesnt have a hydrophobic pocket that encodes a biochemical activity. TPD is a very active research field in academia, biotech and pharma. Current efforts largely focus on two types of degraders: molecular glues and heterobifunctional Proteolysis Targeting Chimeras (PROTACs), both of which come with their inherent challenges. In this project, we want to focus our attention on a third, largely neglected class of small-molecule degraders. These compounds are based on the concept of hydrophobic tagging (HyT) and are supposed to work by binding to the POI and subsequently exposing a hydrophobic feature that mimics local misfolding of the POI. The ensuing mechanisms of molecular recognition that lead to POI degradation are however completely unexplored. We believe that the lack of mechanistic insights in HyT is the biggest bottleneck that holds this modality back. We aim to gain more insight into this topic by connecting functional genomics, biochemistry, and synthetic chemistry. This will enable us to dissect, understand and expand HyT to new targets and hopefully lay the foundation to conceptualize the design of novel medicines in a mechanistically understood manner. In parallel, via investigating the molecular mode of action of the studied small- molecule degraders, we anticipate to gain insights into fundamental mechanisms of protein quality control networks.