A novel AR molecular glue degrader via bivalent engagement of the N-terminal domain and RNF213-UBE2J2 complex

Authors

Wu, K., Wu, Q., Lu, Y., Yang, Q., Ran, T., Zhang, J., Qiu, X., Huang, C., Lin, Y., Chen, J., Yang, Z., Zhang, J., Qin, W., Liu, Z., Liu, X., Tang, M., Chen, H., Zheng, J., Chen, X., Shang, J.

Abstract

Targeted protein degradation enables the elimination of disease-relevant proteins through induced proximity between E3 ligases and substrates. Current androgen receptor (AR) therapies act via the ligand-binding domain (LBD) but fail against constitutively active LBD mutants or splice variants such as AR-V7. Here, we identify GZL626, a small-molecule degrader that induces proteasome-dependent degradation of both full-length AR and AR-V7. GZL626 suppresses AR transcriptional activity, inhibits proliferation of AR-positive prostate cancer cells, and blocks SARS-CoV-2 infection. Mechanistically, GZL626 binds the intrinsically disordered AR N-terminal domain (NTD) and promotes formation of a noncanonical RNF213-UBE2J2-AR ternary complex that drives AR ubiquitination and degradation. The AR DNA-binding domain (DBD) acts as a structural hub within this assembly. Distinct from PROTACs or classical molecular glues, GZL626 engages both AR and RNF213 bivalently, remodeling protein interactions to stabilize a functional E3-E2-substrate complex. These findings establish GZL626 as a first-in-class NTD degrader with potential to overcome resistance in advanced prostate cancer.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 18 Jul 2026.

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