High-throughput ligand diversification to discover chemical inducers of proximity
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 CRL4<sup>CRBN</sup> 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 SCF<sup>FBXO3</sup>, 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.
Authors
- Bryce da Camara
- Timothy R. Bishop (ORCID: https://orcid.org/0000-0002-0321-7809)
- Paige Barta (ORCID: https://orcid.org/0000-0001-6848-0758)
- Zoe Rutter (ORCID: https://orcid.org/0000-0002-7500-2276)
- Daniela V. Wenge (ORCID: https://orcid.org/0000-0002-0064-9104)
- Eric M. Bilotta (ORCID: https://orcid.org/0000-0001-7609-3037)
- Moritz Hunkeler (ORCID: https://orcid.org/0000-0003-0246-1188)
- Trever R. Carter (ORCID: https://orcid.org/0000-0001-5938-4043)
- James B. Shaum (ORCID: https://orcid.org/0000-0003-1664-1091)
- Bruno Melillo (ORCID: https://orcid.org/0000-0002-9708-5287)
- W. He
- Erica Steen
- Lauren M Hargis
- Sydney R. Schweber
- Georg Winter
- Hakyung Cheong
- E. O. Fischer
- Brendan G. Dwyer (ORCID: https://orcid.org/0000-0001-8593-4184)
- Keary M. Engle
- Benjamin F. Cravatt
- Seiya Kitamura
- Hirotake Furihata
- Fabian Offensperger
- Katherine A. Donovan
- Jordan Janowski
- Matthias Hinterndorfer
- Natalia Milosevich
- Michael A. Erb
- Miquel Muñoz i Ordoño
- Scott A. Armstrong
- Alessio Ciulli
- Yanhe Wen
Institutions
- Scripps Research Institute (US)
- Albert Einstein College of Medicine (US)
- Harvard University (US)
- Austrian Academy of Sciences (AT)
- Austrian Research Institute for Artificial Intelligence (AT)
- University of Dundee (GB)
- Dana-Farber Cancer Institute (US)
- CeMM Research Center for Molecular Medicine (AT)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2026-02-16
- DOI
- https://doi.org/10.1038/s41589-025-02137-2
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 22.24