Hijacking Immune-Cell Specific E3 Ligases for Targeted Protein Degradation

ASPIRE Award (2022-Present)

Georg Winter, PhD, CeMM- Research Center for Molecular Medicine (Austria); Steve Gygi, PhD, Harvard Medical School

The burgeoning field of targeted protein degradation holds the promise of drastically expanding the space of druggable targets in cancer and other diseases. Over the last decade, studies have compellingly demonstrated that small molecules with modular design principles can dramatically influence protein stability. These small molecules, termed PROTACs (proteolysis targeting chimeras), can act catalytically to deplete the levels of many targets, including oncoproteins, showcasing their potential as powerful tools in cancer therapeutics. Indeed, there are currently over a dozen PROTACs in clinical trials, with that number increasing each year. However, despite the promise of targeted protein degradation, many obstacles remain which limit the scope of current PROTAC technology. One major limitation is the small number of targetable E3 ubiquitin ligases which have well-characterized small molecule ligands usable for PROTAC design. Finding ligands for tissue-specific E3 ligases is particularly appealing, as tissue-specific PROTACs may have increased efficacy and lower toxicity.

In this ASPIRE award, Georg Winter and Steve Gygi will identify E3 ligases that are specifically expressed in immune cells, and then go on to develop small molecule ligands that bind to those enzymes. They will first use a proteomic approach to find and validate E3 ligases which are only present in immune cells. After identifying the E3 ligases, the team will use a novel platform they previously developed to discover covalent small molecule binders for those proteins. The project’s output will be a set of tool compounds that will enable the next stage for exploration of novel biology, technologies, and therapeutics. By expanding the scope of targetable, specifically immune cell-expressed E3 ligases, they will open the field up to immune-specific modulation with this powerful technology.