ArticleJournal of the American Chemical Society2010
Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.
Article in Journal of the American Chemical Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 152 citations in OpenAlex.
- Structural Principles of Covalent Flavin Modification in Oxidoreductases.Biochemistry · 2026Review
- Histone probes for reader and eraser investigations.Chemical science · 2025Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Histone demethylase inhibitors: developmental insights and current status.Future medicinal chemistry · 2025Review
- Discovery of novel dual-target inhibitors of LSD1/EGFR for non-small cell lung cancer therapy.Acta pharmacologica Sinica · 2025Article
- Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies.Molecules (Basel, Switzerland) · 2024Review
- LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials.Frontiers in pharmacology · 2023Review
- Targeting the LSD1/KDM1 Family of Lysine Demethylases in Cancer and Other Human Diseases.Advances in experimental medicine and biology · 2023Review
- Efficacy of Vafidemstat in Experimental Autoimmune Encephalomyelitis Highlights the KDM1A/RCOR1/HDAC Epigenetic Axis in Multiple Sclerosis.Pharmaceutics · 2022Article
- ComprehensiveACS pharmacology & translational science · 2021Article
- Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets.ACS central science · 2021Article
- Synthesis of artificial substrate based on inhibitor for detecting LSD1 activity.Journal of clinical biochemistry and nutrition · 2020Article
- Examining sterically demanding lysine analogs for histone lysine methyltransferase catalysis.Scientific reports · 2020Article
- Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein.Cell death & disease · 2019Article
- Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A).Acta pharmaceutica Sinica. B · 2019Article
- Jumonji C Demethylases in Cellular Senescence.Genes · 2019Review
- Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer.Frontiers in immunology · 2019Article
- Kinetics, mechanism, and inhibition of monoamine oxidase.Journal of neural transmission (Vienna, Austria : 1996) · 2018Review
- Review
- Design, Synthesis, and In Vitro Evaluation of Novel Histone H3 Peptide-Based LSD1 Inactivators Incorporating α,α-Disubstituted Amino Acids with γ-Turn-Inducing Structures.Molecules (Basel, Switzerland) · 2018Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
LSD1 is a flavin-dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to imines that are hydrolytically cleaved to formaldehyde. In prior studies, it has been shown that monoamine oxidase inhibitory scaffolds such as propargylamines and cyclopropylamines can serve as mechanism-based inactivators of LSD1. Propargylamine-histone H3 peptide analogues are potent LSD1 inhibitors, whereas small molecule antidepressant MAO acetylenic inhibitors like pargyline do not inhibit LSD1. In contrast, the small molecule MAO cyclopropylamine inhibitor tranylcypromine is a time-dependent LSD1 inhibitor but exo-cyclopropylamine-peptide substrate analogue is not. To provide further insight into small molecule versus peptide relationships in LSD1 inhibition, herein we further our analysis of warheads in peptide scaffolds to include the chlorovinyl, endo-cyclopropylamine, and hydrazine-functionalities as LSD1 inactivators. We find that chlorovinyl-H3 is a mechanism-based LSD1 inactivator whereas endo-cyclopropylamine-H3 does not show time-dependent inactivation. The hydrazine-H3 was shown to be the most potent LSD1 suicide inhibitor yet reported, more than 20-fold more efficient in inhibiting demethylation than propargylamine-H3 derivatives. We re-explored MAO antidepressant agent phenelzine (phenethylhydrazine), previously reported to be a weak LSD1 inhibitor, and found that it is far more potent than previously appreciated. We show that phenelzine can block histone H3K4Me demethylation in cells, validating it as a pharmacologic tool and potential lead structure for anticancer therapy.
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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.