Mimicry of molecular glues using dual covalent chimeras

Eden Kapcan, Karolina Krygier, Maya Luz, Nickolas J. Serniuck, Ali Zhang, Jonathan Bramson and Anthony F. Rullo ()
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Eden Kapcan: McMaster University
Karolina Krygier: McMaster University
Maya Luz: McMaster University
Nickolas J. Serniuck: McMaster University
Ali Zhang: McMaster University
Jonathan Bramson: McMaster University
Anthony F. Rullo: McMaster University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract A special class of proximity inducing bifunctional molecules/chimeras called molecular glues leverage positive co-operativity to stabilize ternary complex formation and induce a biological response. Despite their utility, molecular glues remain challenging to rationally design. This is particularly true in the context of inducing cell-cell proximity which involve ternary complexes that comprise non- or negatively interacting proteins. In this work, we develop a dual proximity labeling strategy enabling a chimera to covalently crosslink a non-interacting serum antibody to a tumor surface protein, within a ternary complex. The resultant resistance to dissociation, including in the presence of competitor binding ligands, mimics molecular glue stabilization. We demonstrate these covalent glue mimics (CGMs) can induce cell-cell proximity in three distinct model systems of tumor-immune recognition, leading to significant functional enhancements. Collectively, this work underscores the utility of dual proximal covalent labeling as a potential general strategy to stabilize ternary complexes comprising non-interacting proteins and enforce cell-cell interactions.

Date: 2025
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DOI: 10.1038/s41467-025-58083-z

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