A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (32)
Xiaoju Wang
Michigan Center for Translational Pathology, University of Michigan
Wenyan Liu
Michigan Center for Translational Pathology, University of Michigan
Jiehao Yang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jean Ching-Yi Tien
Michigan Center for Translational Pathology, University of Michigan
Yu Chang
State Key Laboratory of Structural Chemistry, Fujian Provincial Key Laboratory of Materials and Techniques toward Hydrogen Energy, Fujian Institute of Research on the Structure of Matter
Rahul Mannan
Somnath Mahapatra
Yang Zhou
Lihao Gan
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Xuhong Cao
Jiayi Zhou
Vir Biotechnology Inc.
Yuping Zhang
Sharpkate Shaker
Michigan Center for Translational Pathology, University of Michigan
Yichao Huang
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hang Qiao
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Rudana Hamadeh
Michigan Center for Translational Pathology, University of Michigan
Grafton Ervine
Michigan Center for Translational Pathology, University of Michigan
Cynthia Wang
Michigan Center for Translational Pathology, University of Michigan
Fengyun Su
Michigan Center for Translational Pathology, University of Michigan
Rui Wang
Lanbo Xiao
Raghunath Ranga Sudharshan
Department of Computational Medicine and Bioinformatics, University of Michigan
Arvind Rao
Michigan Center for Translational Pathology, University of Michigan
Zaneta Nikolovska-Coleska
Department of Pathology, University of Michigan
Cole Stephens
Medicinal Chemistry Graduate Program, College of Pharmacy, University of Michigan
Lifeng Pan
State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences
James J. Chou
Debashish Sahu
BioNMR Core Facility, Life Sciences Institute, University of Michigan
Jeanne Stuckey
Rogel Cancer Center, University of Michigan
Zhen Wang
Ke Ding
Arul M. Chinnaiyan