Molecular Glue-Induced Homodimerization Drives Targeted CRBN Autodegradation

Chen, L.; Zou, X.; Liang, J.; Wang, J.; Luo, X.; Shi, T.; Liu, X.; Yang, S.; Cao, L.; Sun, Y.; Zhao, Y.; Wei, H.; Jiang, Y.; Su, Z.; Xiong, H.; Luo, C.; LU, W.

doi:10.64898/2026.03.08.710235

bioRxiv · 10.64898/2026.03.08.710235

Molecular Glue-Induced Homodimerization Drives Targeted CRBN Autodegradation

Chen, L.·Zou, X.·Liang, J.·Wang, J.·Luo, X.·Shi, T.·Liu, X.·Yang, S.·Cao, L.·Sun, Y.·Zhao, Y.·Wei, H.·Jiang, Y.·Su, Z.·Xiong, H.·Luo, C.·LU, W.

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Abstract

Molecular glue degraders (MGDs) offer a sophisticated, proximity-based approach to protein modulation. In this study, we introduce LJY-3-60, a novel proximity-inducing agent that unexpectedly triggers the potent and selective autodegradation of CRBN. Evidence from CRISPR-Cas9 screening and IP-MS reveals that this degradation process is strictly governed by the intrinsic CRL4CRBN machinery, independent of any extrinsic E3 recruitment. Through a combination of cellular and biophysical characterizations, we demonstrate that LJY-3-60 acts as a molecular bridge to template CRBN homodimerization. This mechanism is unequivocally elucidated by the atomic-resolution co-crystal structure of the CRBNMidi-LJY-3-60 complex. The structure explicitly delineates the homodimerization interface, revealing how the ligand reorganizes the protein surface to stabilize a non-canonical architecture that drives trans-autoubiquitination and subsequent proteasomal degradation. Furthermore, LJY-3-60 serves as a highly effective, controllable off-switch to mitigate PROTAC-induced toxicity. Ultimately, this work delivers a robust chemical tool for modulating CRBN stability. By demonstrating how a small molecule can functionally mimic an endogenous E3 substrates degron to catalyse targeted autodegradation, this study establishes a rational structural framework for designing the next generation of self-destructive modulators in targeted protein degradation (TPD) therapeutics.

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Chen, L., Zou, X., Liang, J., Wang, J., Luo, X., Shi, T., Liu, X., Yang, S., Cao, L., Sun, Y., Zhao, Y., Wei, H., Jiang, Y., Su, Z., Xiong, H., Luo, C., LU, W.. 2026-03-10. Molecular Glue-Induced Homodimerization Drives Targeted CRBN Autodegradation. https://doi.org/10.64898/2026.03.08.710235

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