Organic Chemistry Seminar: Dr. Nicolas Bery, INSERM
About the Seminar
Development of potent biodegraders for cancer biology and therapy
Targeted protein degradation (TPD) is an emerging therapeutic modality. One of the TPD approaches harnesses the ubiquitin-proteasome system (UPS) to degrade a protein of interest (POI) by bringing it into proximity with an E3 ubiquitin ligase. This can be achieved by two main categories of degraders: small molecule- and protein-based degraders. Protein-based degraders, also known as bioPROTACs or biodegraders, have the potential to overcome some shortcomings of small molecule-based degraders. They consist of a fusion between a POI-specific protein binder (e.g., intracellular antibodies or antibody mimetics) and an E3 ligase domain. Their main advantage is the relative ease of selecting intracellular binders that target hard-to-drug proteins with high affinity and specificity, including those that are post-translationally modified, have specific conformations or are involved in protein-protein interactions. However, not all fusions between the protein binders and E3 ligase domains produce functional biodegraders. Therefore, to identify functional biodegraders, we combine (i) the selection of potent and specific intracellular antibodies (mimetics) by phage display screening and (ii) the direct assessment of the intracellular biodegraders’ functionality by cell-based screening assays. Following this strategy, we identifed several potent protein-based degraders that can specifically deplete hard-to-drug proteins in cancers such as KRAS, the active conformation of the small GTPase RHOB or more recently the cytidine deaminase. We show their efficacy in vitro and in vivo cancer models either as tool to investigate the function of the POI or to directly determine their therapeutic potential in cancer. Ongoing work aims to advance these biodegraders towards clinical application by implementing their delivery into cells and tumors.