Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence

Guocheng Huang; Maria Areli Lorenzana Carrillo; Hua Chen; Runtai Chen; Saba Abbasi Dezfouli; Joseph Nanoa; Dania Rimawi; Alois Haromy; Yuanyuan Zhao; Rohan Mittal; John Lewis; John R. Ussher; Evangelos D. Michelakis; Ronald Moore; Seyed Amirhossein Tabatabaei Dakhili; Gopinath Sutendra; Adam Kinnaird

doi:10.64898/2026.09.03.749302

Cancer BiologybioRxivSep 7, 2026

Preprint

Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence

Guocheng Huang, Maria Areli Lorenzana Carrillo iD, Hua Chen, Runtai Chen iD, Saba Abbasi Dezfouli iD, Joseph Nanoa iD, Dania Rimawi, Alois Haromy iD, Yuanyuan Zhao iD, Rohan Mittal iD, John Lewis, John R. Ussher iD, Evangelos D. Michelakis iD, Ronald Moore, Seyed Amirhossein Tabatabaei Dakhili iD, Gopinath Sutendra iD, Adam Kinnaird

Abstract

Metastatic prostate cancer remains a lethal disease, with most treatments focusing on the androgen receptor (AR) axis. We identified the zinc finger protein 281 (ZNF281) as a previously unrecognized driver of metastatic prostate cancer that promotes both AR-related transcriptional output and distinct AR-independent tumor-promoting pathways. It increases AR expression and acts as a coactivator to promote AR transcriptional activity. Independent of AR, ZNF281 promotes prostate cancer by upregulating SMURF1 to sustain tumor growth and by promoting SNAIL-mediated metastasis. We developed an orally bioavailable, ZNF281 Interfering Molecule (Oral ZIM) that disrupts its DNA binding and AR protein interaction. Knockout of ZNF281 as well as treatment with oral ZIM potently inhibited prostate cancer growth and metastasis in orthotopic xenograft models of castration-sensitive and castration-resistant prostate cancers (without detectable systemic toxicity), and ZIM outperformed enzalutamide treatment in patient-derived prostate cancer organoids.

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