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TitleHigh-throughput diversification of protein-ligand surfaces to discover chemical inducers of proximity.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateSep 4, 2025
AuthorsJames B Shaum / Miquel Muñoz I Ordoño / Erica A Steen / Daniela V Wenge / Hakyung Cheong / Moritz Hunkeler / Eric M Bilotta / Zoe Rutter / Paige A Barta / Abby M Thornhill / Natalia Milosevich / Lauren M Hargis / Jordan Janowski / Timothy R Bishop / Trever R Carter / Bryce da Camara / Matthias Hinterndorfer / Lucas Dada / Wen-Ji He / Fabian Offensperger / Hirotake Furihata / Sydney R Schweber / Charlie Hatton / Yanhe Wen / Benjamin F Cravatt / Keary M Engle / Katherine A Donovan / Bruno Melillo / Seiya Kitamura / Alessio Ciulli / Scott A Armstrong / Eric S Fischer / Georg E Winter / Michael A Erb
PubMed AbstractChemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of ...Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, monovalent, molecular glue-like CIPs have relied predominantly on serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to empirically discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Here, we used sulfur(VI)-fluoride exchange (SuFEx)-based high-throughput chemistry (HTC) to install 3,163 structurally diverse chemical building blocks onto ENL and BRD4 ligands and then screened the crude products for degrader activity. This revealed dHTC1, a potent, selective, and stereochemistry-dependent degrader of ENL. It recruits CRL4 to ENL through an extended interface of protein-protein and protein-ligand contacts, but only after pre-forming the ENL:dHTC1 complex. We also characterized two structurally distinct BRD4 degraders, including dHTC3, a molecular glue that selectively dimerizes the first bromodomain of BRD4 to SCF , an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and actionable cellular effectors of proximity pharmacology.
External linksbioRxiv / PubMed:40950085 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.5 - 2.9 Å
Structure data

47174

9dur

EMDB-47174, PDB-9dur:
Cryo-EM Structure of CRBN:dHTC1:ENL YEATS
Method: EM (single particle) / Resolution: 2.9 Å

PDB-9gy3:
Crystal structure of CRBNmidi in complex with (S)-dHTC1
Method: X-RAY DIFFRACTION / Resolution: 2.5 Å

Chemicals

ChemComp-ZN:
Unknown entry

PDB-1iqt:
Solution structure of the C-terminal RNA-binding domain of heterogeneous nuclear ribonucleoprotein D0 (AUF1)

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsLIGASE / Mammalian / ENL YEATS / CRBN / dHTC1 / CIP / targeted protein degradation / E3 Ligase / TPD / molecular glue / induced proximity

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