2. Academic Validation
  3. Charged molecular glue discovery enabled by targeted degron display

Charged molecular glue discovery enabled by targeted degron display

  • Nat Chem Biol. 2026 Apr 6. doi: 10.1038/s41589-026-02182-5.
Zhe Zhuang # 1,  Woong Sub Byun # 1 2,  Jakub Chrustowicz # 3,  Zuzanna Kozicka 4 5,  Veronica L Li 6,  Dinah M Abeja 7,  Katherine A Donovan 7 8,  Sara Sepic 3 9,  Inchul You 1,  Mikołaj Słabicki 4 5 10,  Eric S Fischer 7 8,  Stephen M Hinshaw 1,  Benjamin L Ebert 4 5,  Brenda A Schulman 11 12,  Nathanael S Gray 13
Affiliations

Affiliations

  • 1 Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
  • 2 College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.
  • 3 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Department of Pathology, Stanford School of Medicine, Department of Chemistry, ChEM-H, and Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Chemistry, School of Natural Sciences, Technical University of Munich, Garching, Germany.
  • 10 Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
  • 11 Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany. schulman@biochem.mpg.de.
  • 12 Department of Chemistry, School of Natural Sciences, Technical University of Munich, Garching, Germany. schulman@biochem.mpg.de.
  • 13 Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, USA. nsgray01@stanford.edu.
  • # Contributed equally.
PMID: 41942733 DOI: 10.1038/s41589-026-02182-5
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.

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