Cryo-EM structure-based discovery of etravirine as a specific inhibitor of PRMT5/pICln protein-protein interaction for prostate cancer treatment.

Authors

Zhixia Chi, Xueyong Xu, Zhihang Shen, Xuehong Deng, Bennett D Elzey, Chenglong Li, Wen Jiang, Chang-Deng Hu

Published in

Journal of enzyme inhibition and medicinal chemistry. Volume 41. Issue 1. Pages 2727844. Epub Sep 08, 2026.

Abstract

Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancers and correlates with poor patient survival. In prostate cancer, PRMT5 cooperates with its cofactor pICln to promote tumour growth by epigenetically activating androgen receptor (AR) expression. Using a near-atomic cryo-EM structure of PRMT5/MEP50/pICln complex, we identified a previously undefined, pICln-specific protein-protein interaction (PPI) interface on PRMT5, termed P4I. Structure-based virtual screening identified the FDA-approved compound etravirine as a binder to this site. BiFC, Co-IP, and PLA assays confirmed that etravirine disrupts PRMT5/pICln interaction. A cryo-EM structure of PRMT5/MEP50/etravirine further validated on-target binding at P4I. Functionally, etravirine reduced prostate cancer cell proliferation, inhibited tumour growth, and downregulated AR and AR-V7 expression in cells and in mouse models. These results demonstrate that the unique P4I interface is a promising therapeutic target and that etravirine serves as a proof-of-concept lead compound for exploring the potential of P4I-targeted strategies in prostate cancer.

PMID:
42710907
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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