Authors
Xiaoju Wang, Wenyan Liu, Jiehao Yang, Jean Ching-Yi Tien, Yu Chang, Rahul Mannan, Somnath Mahapatra, Yang Zhou, Lihao Gan, Xuhong Cao, Jiayi Zhou, Yuping Zhang, Sharpkate Shaker, Yichao Huang, Hang Qiao, Rudana Hamadeh, Grafton Ervine, Cynthia Wang, Fengyun Su, Rui Wang, Lanbo Xiao, Raghunath Ranga Sudharshan, Arvind Rao, Zaneta Nikolovska-Coleska, Cole Stephens, Lifeng Pan, James J Chou, Debashish Sahu, Jeanne Stuckey, Zhen Wang, Ke Ding, Arul M Chinnaiyan
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 28. Pages e2537437123. Jul 14, 2026. Epub Jul 07, 2026.
Abstract
The TMPRSS2:ERG gene fusion, present in approximately 50% of prostate cancers in patients of European ancestry, drives oncogenesis through aberrant overexpression of the ERG transcription factor. Despite its role as a truncal oncogenic driver, ERG has been considered undruggable due to the absence of enzymatic activity and apparent lack of ligandable pockets. Here, we demonstrate continued dependency on ERG in metastatic prostate cancer and identify a druggable pocket within its N-terminal Pointed (PNT) domain. Using an inducible shRNA system in TMPRSS2:ERG-positive VCaP cells, we show that ERG depletion causes profound growth inhibition. To therapeutically exploit this vulnerability, we conducted a domain-focused differential scanning fluorimetry screen targeting the ERG PNT domain, followed by structure-activity relationship optimization. This approach yielded PBITE-1 (PNT-Binding Inhibitor of the Transcription factor ERG), a small molecule that selectively binds the ERG PNT domain. NMR chemical-shift perturbation mapping and molecular docking revealed that PBITE-1 engages a discrete, solvent-exposed surface comprising two α-helices and an adjacent flexible loop, defining a ligand-binding pocket within the PNT domain. In cellular models, PBITE-1 directly engaged ERG, selectively inhibited proliferation and invasion, and induced apoptosis in ERG-driven prostate and hematologic malignancies. PBITE-1 potently suppressed growth of ERG-positive mouse and human-derived prostate cancer organoids. Furthermore, PBITE-1 treatment significantly induced tumor cell apoptosis in VCaP xenograft models. These findings establish the ERG PNT domain as ligandable and provide preclinical evidence that ERG is directly targetable by small molecules, enabling future development of ERG-directed inhibitors and targeted protein degraders.
PMID:
42412946
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.
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