Inside the cell, proteins are the essential workhorses, driving everything from metabolism to immune defense. To maintain health, cells employ a quality-control system that identifies and removes damaged or unnecessary proteins. Central to this system are E3 ligases, a family of over 600 members that selectively target proteins for degradation.

Targeted protein degradation (TPD) is a promising drug modality that hijacks E3 ligases to eliminate disease-causing proteins. By using small molecules to bridge a target protein with an E3 ligase, we can redirect the cell’s quality-control system to destroy the prime drivers of diseases. The rapid progress of TPD therapeutics into late-stage clinical trials highlights its potential to transform drug discovery.

Despite this promise, a major bottleneck remains. Although humans have 600+ E3 ligases, fewer than 2% have been used in drug development. Most E3 ligase binders to date have been discovered serendipitously, and rationally designing small molecules that bind E3 ligases remains challenging.

We propose a covalent trapping strategy to bypass this limitation. By forming a stable, permanent bond with an E3 ligase, our small molecules can trap E3 ligases, even when they lack a well-defined binding pocket for small molecules. We have identified a chemical scaffold that reproducibly degrades disease-driving proteins across diverse therapeutic areas:

• Androgen receptor: Prostate cancer

• Leucine-rich repeat kinase: Parkinson’s disease

• BCR-ABL: Chronic myelogenous leukemia