BIFI TALK: CRISTINA MAYOR RUIZ

Title: Targeted protein degradation: Chasing molecular glues and coping with resistance to degraders

Abstract:

Targeted protein degradation is a pharmacological strategy based on drugs (degraders) that destroy proteins by hijacking the intracellular proteolysis machinery. This strategy has garnered significant attention in the last year owing to its potential to modulate the abundance of proteins that are difficult to target with conventional inhibitors. Degraders can be multivalent (PROTACs) or monovalent (molecular glue degraders) depending on the number of chemical warheads. Molecular glue degraders offer a promising strategy for targeting disease-relevant proteins that were previously considered “undruggable”. Mechanistically, they orchestrate direct protein-protein interactions between a target protein and an E3 ubiquitin ligase.  As a result, the target protein gets ubiquitinated and then degraded by the proteasome. Despite their great therapeutic potential, the discovery of molecular glue degraders has been largely serendipitous. I will discuss our efforts to facilitate the rational development of molecular glues.

In addition, many genetic determinants governing degrader efficiency have been mapped in recent years, bringing important lessons about resistance mechanisms. Our recent chemoproteomics journey aimed at identifying strategies to overcome broad resistance to degraders will be presented.

FRIDAY, 24th November 2023, 12:00 h
Edificio I+D (Conference room)