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  3. High-throughput ligand diversification to discover chemical inducers of proximity

High-throughput ligand diversification to discover chemical inducers of proximity

  • Nat Chem Biol. 2026 Feb 16. doi: 10.1038/s41589-025-02137-2.
James B Shaum # 1,  Miquel Muñoz I Ordoño # 2 3,  Erica A Steen 1,  Daniela V Wenge 4,  Hakyung Cheong 5,  Jordan Janowski 1,  Moritz Hunkeler 5 6,  Eric M Bilotta 1,  Zoe J Rutter 7,  Paige A Barta 1,  Abby M Thornhill 5,  Natalia Milosevich 1,  Lauren M Hargis 1,  Timothy R Bishop 1,  Trever R Carter 1,  Bryce da Camara 1,  Matthias Hinterndorfer 2,  Lucas Dada 8,  Wen-Ji He 1,  Fabian Offensperger 2,  Hirotake Furihata 7,  Sydney R Schweber 4,  Charlie Hatton 4,  Yanhe Wen 4,  Benjamin F Cravatt 1,  Keary M Engle 1,  Katherine A Donovan 5 6,  Bruno Melillo 1,  Seiya Kitamura 8,  Alessio Ciulli 7,  Scott A Armstrong 4,  Eric S Fischer 5 6,  Georg E Winter 9 10,  Michael A Erb 11
Affiliations

Affiliations

  • 1 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria.
  • 4 Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 7 Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
  • 8 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
  • 9 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at.
  • 10 AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at.
  • 11 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. michaelerb@scripps.edu.
  • # Contributed equally.
PMID: 41699285 DOI: 10.1038/s41589-025-02137-2
Abstract

Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, Molecular Glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein-ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4CRBN complex through an extended interface of protein-protein contacts and only engages CRBN after pre-forming the ENL:dHTC1 complex. We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCFFbxo3, an E3 Ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology.

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