ArticleJournal of medicinal chemistry2016
Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.
Article in Journal of medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed.
- Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.Journal of chemical information and modeling · 2025Article
- Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts.Journal of medicinal chemistry · 2023Article
- Recent Advances with KDM4 Inhibitors and Potential Applications.Journal of medicinal chemistry · 2022Review
- Activation of Xist by an evolutionarily conserved function of KDM5C demethylase.Nature communications · 2022Article
- Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer.Journal of biomedical science · 2022Article
- Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores.ACS medicinal chemistry letters · 2022Article
- The emerging role of KDM5A in human cancer.Journal of hematology & oncology · 2021Review
- Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.bioRxiv : the preprint server for biology · 2020Article
- A New Family of Jumonji C Domain-Containing KDM Inhibitors Inspired by Natural Product Purpurogallin.Frontiers in chemistry · 2020Article
- Application of Fragment-Based Drug Discovery to Versatile Targets.Frontiers in molecular biosciences · 2020Review
- In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment.ACS medicinal chemistry letters · 2019Article
- Structure-Based Screening of Tetrazolylhydrazide Inhibitors versus KDM4 Histone Demethylases.ChemMedChem · 2019Article
- Article
- Small molecule KDM4s inhibitors as anti-cancer agents.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Inhibitors of Protein Methyltransferases and Demethylases.Chemical reviews · 2018Review
- Computer-Aided Drug Design in Epigenetics.Frontiers in chemistry · 2018Review
- Synthesis and Demonstration of the Biological Relevance of spChemistry (Weinheim an der Bergstrasse, Germany) · 2017Article
- Histone Lysine Demethylase Inhibitors.Cold Spring Harbor perspectives in medicine · 2017Review
- Twenty years on: the impact of fragments on drug discovery.Nature reviews. Drug discovery · 2016Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼ 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
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Registered trials
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.