Direct-to-Biology Enabled Molecular Glue Discovery

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 <i>de novo</i> molecular glue discovery lies within kinetic profiling of unpurified mixtures of small organic molecules against protein pairs.

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Publication Details

Journal
Journal of the American Chemical Society
Published
2025-12-24
DOI
https://doi.org/10.1021/jacs.5c13496
Citations
5
Primary Topic
Chemical Synthesis and Analysis
Type
article
Field-Weighted Citation Impact
4.03
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article

Direct-to-Biology Enabled Molecular Glue Discovery

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5 citations
Journal of the American Chemical Society
Chemical Synthesis and Analysis
4.03
article

Direct-to-Biology Enabled Molecular Glue Discovery

Anup Aggarwal, Gisele Nishiguchi, Marcus Fischer, Marisa Actis, Daniel J. Blair, Kevin McGowan, Maowei Hu, Anand Mayasundari, Jamie Jarusiewicz, Anang A. Shelat, Brandon Young, Shea Mercer, Meng Zhang, Jun Yang, Sarah M. Young, Uma Neelakantan, M. Madan Babu, Satoshi Yoshimura, Jason Ochoada, Lei Yang, Yong Li, Logan McGrath
article en
5 citations

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 <i>de novo</i> molecular glue discovery lies within kinetic profiling of unpurified mixtures of small organic molecules against protein pairs.

Journal of the American Chemical SocietyVol. 148(1)
St. Jude Children's Research Hospital (US), Target (United States) (US), Lead Discovery Center (Germany) (DE), G1 Therapeutics (United States) (US), Io Therapeutics (United States) (US), Center for Discovery (US)
Openalex Percentile: Top 6%
Chemical Synthesis and Analysis
4.03
DOIOpen Access PDFOpenAlex
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