Targeting E3 ubiquitin ligases with small molecules

E3 ubiquitin ligases are enzymes within the ubiquitin-proteasome system (UPS) that catalyse the transfer of ubiquitin to specific substrate proteins. Targeting of E3 ligases with small molecules is a frontier goal of chemical biology and drug discovery because it allows: 1) enhanced selective intervention in the UPS, compared for example to proteasome inhibitors; 2) co-opting the UPS to induce the degradation of new target proteins. For example, E3 ligase ligands can be incorporated into bifunctional chimeric molecules, nick-named proteolysis targeting chimeras (PROTACs), that induce protein ubiquitination and subsequent degradation inside the cell. However, only few E3 ligases have been successfully targeted with small molecules, and this requires the targeting of proteins surfaces or protein-protein interactions that are difficult-to-target (1).
The Ciulli lab works on developing E3 ligase targeting ligands and PROTACs. They have pioneered the structure-guided design and optimization of molecules targeting the von Hippel-Lindau (VHL) E3 ligase. They qualified potent and selective VHL inhibitor VH298 as a chemical probe of the VHL-HIF axis in the hypoxia signaling pathway. Moreover, they have shown how the VHL ligands can be successfully conjugated to a variety of protein-targeting ligands, yielding PROTACs active against diverse target proteins in cells and in vivo (2).
The Virdee lab has pioneered the development of novel chemical reagents and tools for studying the UPS, with a particular focus on E3 ligases. A key achievement is the development of probes that measure the hallmark trans-thiolation activity of ubiquitination enzymes. These have been used to gain insights into disease relevant E3 regulation and have potential as biomarkers for diseases of unmet clinical need. Application of these technologies has led to the identification of a new class of E3 ligase with non-lysine ubiquitination activity (3).
This project aims to develop novel small molecule binders for new E3 ligases of biological and therapeutic relevance. The project is designed as highly interdisciplinary, drawing on complementary expertise from both the Ciulli lab and Virdee labs. The student will receive outstanding training in multidisciplinary areas in cutting-edge research in fundamental and translational chemical and structural biology from both the Ciulli and Virdee labs.
References
1. Bulatov E, Ciulli A. Biochem J 2015; 467:365-86.
2. Maniaci C, Ciulli A. Curr Opin Chem Biol 2019; 52:145-56.
3. Pao K-C et al. Nature 2018; 556:381-5.