UC Berkeley

Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy that co-opts the cell’s endogenous ubiquitin-proteasome system to selectively eliminate disease-causing proteins. Unlike traditional occupancy-driven inhibitors, which are limited to roughly 10% of the proteome featuring identifiable binding pockets or catalytic active site, TPD modalities operate through an event-driven and catalytic mechanism, inducing proximity between an E3 ubiquitin ligase and a protein of interest to promote its ubiquitination and proteasomal degradation at sub-stoichiometric concentrations. Molecular glue degraders in particular represent a compelling TPD approach, offering superior drug-like properties by virtue of their lower molecular weights and linker-less architecture, while enabling engagement of shallow binding surfaces of proteins previously deemed “undruggable”. However, the rational design of molecular glue degraders remains a central challenge in the field as most known degraders were identified serendipitously or through phenotypic screens and the structural principles governing a productive E3 ligase-degrader-target ternary complex formation are still poorly understood. In this dissertation, we sought to address this gap by identifying transplantable covalent chemical handles that could be appended onto the exit vectors of existing protein-targeting ligands to convert them into monovalent degraders of their respective targets. Using the BET family inhibitor JQ1 as a testing platform, we synthesized and screed a series of covalent JQ1 analogs and identified a vinylsulfonyl piperazine moiety that, when appended onto JQ1, enabled potent and selective proteasomal degradation of BRD4. Chemoproteomic profiling revealed that this handle covalently engages C119 on DCAF16, a CUL4 substrate receptor, as the E3 ligase responsible for the BRD4 degradation. This DCAF16-recruiting handle was successfully transplanted across a chemically diverse panel of protein-targeting ligands to induce the degradation of CDK4, the androgen receptor, BTK, SMARCA2/4, and BCR-ABL/c-ABL, spanning multiple protein classes. Together, these findings established a generalizable framework for a target-centric molecular glue degrader design that expands the repertoire of ligandable E3 ligases beyond the extensively exploited CRL4CRBN and VHL.