8JIG

A Novel UHRF1-Targeted Compound

Summary for 8JIG

• Entry DOI: 10.2210/pdb8jig/pdb
• Descriptor: E3 ubiquitin-protein ligase UHRF1, N-[2,4-bis(oxidanylidene)-1H-pyrimidin-5-yl]-N'-oxidanyl-octanediamide (3 entities in total)
• Functional Keywords: uhrf1, prostate cancer, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 48135.70

Authors

Chen, Y.,Jiang, L. (deposition date: 2023-05-26, release date: 2024-05-29, Last modification date: 2025-12-10)

Primary citation

Fu, Y.,Jiang, L.,Xie, G.,Peng, Y.,Fu, Y.,Zhu, Q.,Liu, Y.,Zhao, G.,Liu, X.,Peng, Y.,Chen, Y.,Li, X.
A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization.
Commun Chem, 8:356-356, 2025

PubMed Abstract: UHRF1 is a pivotal epigenetic regulator bridging DNA methylation and histone modifications, frequently overexpressed in prostate cancer (PCa). However, no UHRF1-targeted therapeutics have advanced to clinical trials. Here, we report the development of H93, a hybrid small molecule integrating functional groups derived from NSC232003 and vorinostat, respectively. H93 exhibits potent anticancer activity in vitro, correlating with UHRF1 protein abundance, and co-crystallization studies confirm that H93 directly binding to the SRA domain of UHRF1. Intriguingly, H93 promotes UHRF1 dimerization, generating a defined binding pocket that stabilizes compound engagement and enhances druggability of UHRF1 as a non-kinase target. Dimerized UHRF1 adopts a "closed" conformation that disrupts its interaction with DNMT1, impairs DNA methylation maintenance, and reactivates epigenetically silenced tumor suppressor genes. In vivo, H93 demonstrates significant antitumor efficacy. Overall, this study elucidates the structural and mechanistic basis of H93, establishing it as a promising UHRF1-targeted therapy for PCa.

PubMed: 41254147
DOI: 10.1038/s42004-025-01744-3

Experimental method

X-RAY DIFFRACTION (2.4 Å)