415: ERG Unlocked: Targeting the PNT Domain with PBITE-1

PNAS - This episode breaks down a PNAS study that identifies a druggable pocket in the ERG transcription factor PNT domain and describes PBITE-1, a small-molecule probe that binds this pocket to inhibit ERG-driven prostate cancer models. Key terms: ERG, PNT domain, PBITE-1, prostate cancer, small-molecule inhibitor. Study Highlights:The authors show that TMPRSS2:ERG-positive prostate cancer cells remain dependent on ERG for survival and tumor maintenance. A domain-focused DSF screen identified F0341 as a PNT-domain binder and SAR optimization yielded PBITE-1, which engages a solvent-exposed pocket spanning two helices and a flexible loop. PBITE-1 selectively stabilizes ERG in cells, suppresses ERG target genes, reduces proliferation and invasion, induces apoptosis in ERG-positive cell lines and organoids, and triggers tumor cell apoptosis in VCaP xenografts. Conclusion:The ERG N-terminal PNT domain contains a structurally coherent, ligandable pocket; PBITE-1 provides proof-of-concept that ERG can be directly targeted by small molecules, laying groundwork for future ERG-directed inhibitors and degrader strategies for TMPRSS2:ERG-driven cancers. Music:Enjoy the music based on this article at the end of the episode. Article title:A ligandable PNT domain establishes ERG as a directly targetable oncogenic driver in prostate cancer Journal:PNAS DOI:10.1073/pnas.2537437123 Reference:https://doi.org/10.1073/pnas.2537437123 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/erg-pnt-pbite-1 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-07-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing ERG dependency in TMPRSS2:ERG-positive prostate cancer, DSF screening and hit identification (F0341), SAR optimization to PBITE-1, binding and target engagement assays (NMR, BLI, CETSA), cellular effects (viability, apoptosis, ERG target gene suppression), organoid and in vivo- transcript topics: ERG dependency in TMPRSS2:ERG-positive prostate cancer; Domain-focused differential scanning fluorimetry (DSF) screen; PBITE-1 discovery and SAR optimization; PBITE-1 binding interface mapping to ERG PNT domain (NMR, docking, H2/H6); Target engagement and cellular effects (CETSA, cell viability, apoptosis, ERG target genes); Organoid and in vivo VCaP xenograft data QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- TMPRSS2:ERG fusion occurs in approximately 50% of prostate cancers in patients of European ancestry.- PBITE-1 engages a discrete solvent-exposed surface within the ERG PNT domain, defining a ligand-binding pocket.- PBITE-1 directly binds the ERG PNT domain and stabilizes full-length ERG in cell...