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bioRxiv · 10.64898/2026.11.13.762685

Discovery of molecular glues for modulating MHC presentation of cancer neoantigens

Shen, W.·Zhang, Z.·He, C.·Guiley, K. Z.·Lashkari, V. D.·Hernandez, J.·Bruno, P. M.·Shokat, K. M.
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Abstract

Antigen presentation by MHC class I molecules is essential for cancer immunosurveillance, but many cancer-specific antigens fail to form complexes with Class I MHC and are poorly presented on the cell surface. In this study, we present a chemical strategy to overcome this limitation by identifying peptide MHC glues (PMGs) that promote the formation of peptide-MHC complexes with otherwise unpresentable cancer antigens. Crystal structures of these complexes show that our compounds stabilize antigen-MHC binding by making simultaneous interactions with the MHC protein and the antigen peptides. These findings reveal a new approach for chemically rewiring Class I MHC antigen presentation and accessing rare cancer antigens for therapeutic targeting.

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Shen, W., Zhang, Z., He, C., Guiley, K. Z., Lashkari, V. D., Hernandez, J., Bruno, P. M., Shokat, K. M.. 2026-11-14. Discovery of molecular glues for modulating MHC presentation of cancer neoantigens. https://doi.org/10.64898/2026.11.13.762685

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