ArticleBiochemistry2022
Discovery and Mechanism of Small Molecule Inhibitors Selective for the Chromatin-Binding Domains of Oncogenic UHRF1.
Article in Biochemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Sodium Channel Blockers Demonstrate Binding Affinity for the Tandem Tudor Domain of the Epigenetic Hub UHRF1.ChemMedChem · 2026Article
- A Hybrid compound H93 treats prostate cancer by directly binding UHRF1 and promoting protein dimerization.Communications chemistry · 2025Article
- Negative Cooperativity in the UHRF1 TTD-PHD Dual Domain Masks the Contributions of Cation-π Interactions between Trimethyllysine and the TTD Aromatic Cage.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024Review
- Oncogenic Roles of UHRF1 in Cancer.Epigenomes · 2024Review
- Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.Nature communications · 2024Article
- Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening.RSC chemical biology · 2024Article
- Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors.ACS medicinal chemistry letters · 2023Article
- Natural and Synthetic Anticancer Epidrugs Targeting the Epigenetic Integrator UHRF1.Molecules (Basel, Switzerland) · 2023Review
- Chemical tools targeting readers of lysine methylation.Current opinion in chemical biology · 2023Review
- Large-Scale Chromatin Rearrangements in Cancer.Cancers · 2022Review
- The UHRF protein family in epigenetics, development, and carcinogenesis.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2022Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Chromatin abnormalities are common hallmarks of cancer cells, which exhibit alterations in DNA methylation profiles that can silence tumor suppressor genes. These epigenetic patterns are partly established and maintained by UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1), which senses existing methylation states through multiple reader domains, and reinforces the modifications through recruitment of DNA methyltransferases. Small molecule inhibitors of UHRF1 would be important tools to illuminate molecular functions, yet no compounds capable of blocking UHRF1-histone binding in the context of the full-length protein exist. Here, we report the discovery and mechanism of action of compounds that selectively inhibit the UHRF1-histone interaction with low micromolar potency. Biochemical analyses reveal that these molecules are the first inhibitors to target the PHD finger of UHRF1, specifically disrupting histone H3 arginine 2 interactions with the PHD finger. Importantly, this unique inhibition mechanism is sufficient to displace binding of full-length UHRF1 with histones in vitro and in cells. Together, our study provides insight into the critical role of the PHD finger in driving histone interactions, and demonstrates that targeting this domain through a specific binding pocket is a tractable strategy for UHRF1-histone inhibition.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.