Discovery of Novel Molecular Glues and Targeted Protein Degradation Mechanisms for Cancer Therapeutics

Abstract

Targeted protein degradation has emerged as a promising therapeutic approach that recruits cellular degradation machineries to induce degradation of target proteins. However, the mechanisms underlying many small molecule degraders, particularly monomeric protein degraders, remain poorly understood. This lack of understanding hinders optimization of these degraders' efficacy and rational discovery and design of new degraders for specific targets. To address this gap, I aimed to discover and characterize novel molecular glue and targeted protein degradation mechanisms throughout my PhD research. My thesis work includes three projects that leverage functional genomic screens to deconvolve ubiquitin ligases involved in drug-induced degradation systems. In chapter 2, I led the discovery of a new class of DCAF16-based covalent BRD4 molecular glue degraders and their novel "template-assisted covalent mechanism" of activity. In chapter 3, I contributed to the identification and mechanistic characterization of the first substrate receptor independent molecular glue degrader CR8, and in chapter 4, I discovered a dichotomy of ubiquitin ligase mechanism between two classes of selective estrogen receptor degraders. These results provide a deeper understanding of molecular glue and targeted protein degradation mechanisms, which can potentially enable the discovery and development of future protein degrader drugs.