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Chemical Structural Biology and Drug Discovery of Targeted Protein Degradation

The Ciulli Laboratory develops novel small molecules inducing targeted protein degradation and modulating protein-protein interactions. We do research on fundamental chemical biology and translate it via collaboration partnership with the biopharma industry and by creation of spin-out companies.

Pioneering discoveries from the Laboratory and others over the past decade have contributed to the advent of a new modality of chemical intervention to study biology and drugs to cure disease. Instead of blocking a target protein as conventionally done with inhibitors, we are designing “tailored” bifunctional molecules that bring a target protein to an E3 ubiquitin ligase for targeted protein degradation. We have illuminated important understanding of how this new class of molecules work that is beginning to define the rules and principles of how to design and study them.

Our research in this area takes a multidisciplinary approach including organic and medicinal chemistry and computational tools to design and achieve desired molecules; structural biology and biophysics to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and chemical biology, biochemistry, proteomics and cell biology to study the cellular impact of our small molecules into relevant cellular systems and disease models, in collaboration with biologists and medics.

Current research efforts are directed towards:

1. Design and development of PROTACs as chemical tools for probing the biological function and therapeutic potential of compelling targets in cancer and other diseases

2. Structure-guided fragment-based design of novel E3 ligase binding ligands

3. Biochemical, biophysical and structural studies of novel E3 ubiquitin ligases

4. Novel approaches to small-molecule inducible degron technologies

Funding