Direct-to-Biology Enabled Molecular Glue Discovery

  • J Am Chem Soc. 2026 Jan 14;148(1):20-27. doi: 10.1021/jacs.5c13496.
Maowei Hu  1 ,  Jason Ochoada  2 ,  Marisa Actis  3 ,  Kevin McGowan  4 ,  Jamie A Jarusiewicz  3 ,  Satoshi Yoshimura  5 ,  Logan McGrath  5 ,  Uma Neelakantan  1  6 ,  Anup Aggarwal  3 ,  Anand Mayasundari  3 ,  Sarah M Young  1 ,  Meng Zhang  6 ,  Lei Yang  7 ,  Yong Li  7 ,  Shea Mercer  8 ,  M Madan Babu  6 ,  Marcus Fischer  1 ,  Brandon M Young  4 ,  Jun J Yang  5 ,  Gisele Nishiguchi  3 ,  Anang A Shelat  2 ,  Daniel J Blair  1
Affiliations
  • 1. Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 2. Lead Discovery Informatics Center, Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3. Targeted Protein Degradation Center, Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38015, United States.
  • 4. Medicinal Chemistry Center, Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5. Department of Pharmacy and Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 6. Center of Excellence for Data Driven Discovery, Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 7. Analytical Technologies Center, Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 8. Program Management, Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38015, United States.
PMID: 41443594 DOI: 10.1021/jacs.5c13496
Abstract

Molecular Glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for function-first identification of molecular gluing events. In the widely accepted mechanism, a molecular glue stabilizes two proteins within a ternary complex─here, we show how differences in affinity for ternary and binary complexes directly categorize glues from nonglues. We leverage these differences together with high-throughput chemical synthesis and affinity-selection mass-spectrometry to discover a molecular glue from a suite of over 20,000 crude chemical reaction mixtures. Orthogonal assays robustly support the identification of Molecular Glues via ternary complex stability. Our findings suggest that a roadmap for de novo molecular glue discovery lies within kinetic profiling of unpurified mixtures of small organic molecules against protein pairs.

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