UC Berkeley

One of the largest obstacles in modern drug discovery is that a significant portion (>90%) of the proteome is considered “undruggable”, in that these proteins lack a characterized, functional binding pocket or “ligandable hotspot” which small molecules can bind to and modulate the protein’s function for therapeutic benefit. To overcome such disease-causing proteins, targeted protein degradation (TPD) strategies have arisen, where the cell’s endogenous degradation machinery is hijacked to ubiquitinate and degrade the classically undruggable protein. Molecular glue degraders serve as a promising modality to achieve TPD. These are monovalent compounds that induce the proximity of a target protein with a component of the ubiquitin proteasome system to degrade the protein of interest. The systematic and modular synthesis of such small molecules, however, has not been possible due to a lack of known rational chemical design principles for converting protein-targeting ligands into molecular glue degraders.

This dissertation discusses the elucidation of novel design principles for the synthesis of covalent molecular glue degraders through the discovery of a transplantable chemical moiety that converts protein-targeting ligands into monovalent degraders of their corresponding targets. We first discovered a covalent handle which, when appended to the CDK4/6 inhibitor ribociclib, resulted in the degradation of CDK4 in a proteasome-dependent manner. Structural optimization of the initial covalent handle led to the synthesis of a but-2-ene-1,4-dione (fumarate) moiety that induced a more potent dose-responsive degradation of CDK4. Utilizing quantitative chemoproteomic platforms to profile global cysteine reactivity throughout the proteome, we identified that the RING-family E3 ligase RNF126 was binding covalently to the monovalent CDK4 degraders. Transplanting this covalent fumarate handle onto various inhibitors and protein-targeting ligands allowed for the degradation of protein targets BCR-ABL and c-ABL, PDE5, SMARCA2/4, LRRK2, BRD4, BTK, HDAC1/3, and AR and AR-V7. We have identified a first-in-class minimal covalent chemical handle that can convert protein targeting ligands into molecular glue degraders of their corresponding targets across diverse chemical and protein classes.