Zhe Zhuang, Woong Sub Byun, Jakub Chrustowicz, Zuzanna Kozicka, Veronica Lynn Li, Dinah M Abeja, Katherine A. Donovan, Sara Sepic, Inchul You, Mikołaj Słabicki, Eric S. Fischer, Stephen M. Hinshaw, Benjamin L. Ebert, Brenda A. Schulman, Nathanael S. Gray
Abstract Small molecules that induce protein interactions hold tremendous potential as new medicines, probes for molecular pathways and tools for agriculture. Explosive growth of targeted protein degradation drug development has spurred renewed interest in proximity-inducing molecules, especially molecular glue degraders (MGDs). These compounds catalyze the destruction of disease-causing proteins by reshaping protein surfaces and promoting cooperative binding between ubiquitylating enzymes and target proteins. MGD discovery for predefined targets is a major challenge in contemporary drug discovery. Here, we solve this important chemical challenge through ‘chemocentric’ MGD discovery of ZZ1, a BET-family protein degrader and a prodrug of a negatively charged glue. ZZ1 activation unmasks a sulfinic acid that binds the modular CTLH ubiquitin ligase complex through a basic pocket in its YPEL5 subunit. These findings demonstrate a previously unrecognized capacity of YPEL5 to recruit CTLH substrates and enable the discovery of MGDs for exceedingly common acidic and basic degrons.