Abstract

My lab’s research interests are on the development of small molecules targeting protein-protein interactions (PPIs) and inducing protein degradation. Over the past 10 years, my group has made significant contributions to selective chemical intervention on important PPI targets. Initially in collaboration with the Crews Lab, we pioneered the structure-guided design of drug-like ligands for the von Hippel-Lindau E3 ligase, and later in independent work reported one of the first degrader molecules originated from their VHL ligands. These discoveries jump-started the PROTAC field and led to significant commercial impact across academia and biopharma worldwide. More recently, we have illuminated important structural and mechanistic insights into the molecular recognition and mechanism of action of PROTAC degrader molecules, contributing to making targeted protein degradation a realistic and effective drug discovery modality.

Building on these pioneering discoveries, we have partnered with Boehringer Ingelheim to develop structure-based PROTAC design as a novel disruptive approach to induce the degradation of undruggable cancer targets. I will present our recent successful campaign developing degraders against the BAF complex ATPase subunits SMARCA2 and SMARCA4 as a strategy to explore compelling vulnerabilities and dependencies in cancers.1

References
1. Farnaby, W. et al. Nat. Chem. Biol. https://doi.org/10.1038/s41589-
019-0294-6 (2019).