2. Academic Validation
  3. Direct-to-Biology Enabled Molecular Glue Discovery

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

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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