赖氨酸特异性去甲基化酶1（LSD1）的组蛋白去甲基化酶检测与抑制
LSD1 Histone Demethylase Assays and Inhibition.
作者信息
Hayward D, Cole P A
机构信息
Johns Hopkins School of Medicine, Baltimore, MD, United States.
Johns Hopkins School of Medicine, Baltimore, MD, United States.
出版信息
Methods Enzymol. 2016;573:261-78. doi: 10.1016/bs.mie.2016.01.020. Epub 2016 Feb 23.
Abstract
The lysine-specific demethylase (LSD1) is a flavin-dependent amine oxidase that selectively removes one or two methyl groups from histone H3 at the Lys4 position. Along with histone deacetylases 1 and 2, LSD1 is involved in epigenetically silencing gene expression. LSD1 has been implicated as a potential therapeutic target in cancer and other diseases. In this chapter, we discuss several approaches to measure LSD1 demethylase activity and their relative strengths and limitations for inhibitor discovery and mechanistic characterization. In addition, we review the principal established chemical functional groups derived from monoamine oxidase inhibitors that have been investigated in the context of LSD1 as demethylase inhibitors. Finally, we highlight a few examples of recently developed LSD1 mechanism-based inactivators and their biomedical applications.
摘要
赖氨酸特异性去甲基化酶（LSD1）是一种黄素依赖性胺氧化酶，可选择性地从组蛋白H3的赖氨酸4位点去除一个或两个甲基基团。LSD1与组蛋白去乙酰化酶1和2一起，参与基因表达的表观遗传沉默。LSD1已被认为是癌症和其他疾病的潜在治疗靶点。在本章中，我们讨论了几种测量LSD1去甲基化酶活性的方法，以及它们在抑制剂发现和机制表征方面的相对优势和局限性。此外，我们回顾了从单胺氧化酶抑制剂衍生而来的主要已确立的化学官能团，这些官能团已在LSD1作为去甲基化酶抑制剂的背景下进行了研究。最后，我们重点介绍了一些最近开发的基于LSD1机制的失活剂及其生物医学应用。
相似文献
1
LSD1 Histone Demethylase Assays and Inhibition.
Methods Enzymol. 2016;573:261-78. doi: 10.1016/bs.mie.2016.01.020. Epub 2016 Feb 23.
2
Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors.
J Am Chem Soc. 2010 Mar 10;132(9):3164-76. doi: 10.1021/ja909996p.
3
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. 2018 May 6;23(5):1099. doi: 10.3390/molecules23051099.
4
Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators.
J Med Chem. 2016 Feb 25;59(4):1531-44. doi: 10.1021/acs.jmedchem.5b01323. Epub 2016 Jan 4.
5
Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors.
Bioorg Med Chem. 2018 Feb 1;26(3):775-785. doi: 10.1016/j.bmc.2017.12.045. Epub 2018 Jan 2.
6
Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1.
PLoS One. 2017 Feb 3;12(2):e0170301. doi: 10.1371/journal.pone.0170301. eCollection 2017.
7
Design, synthesis and biological activity of 3-oxoamino-benzenesulfonamides as selective and reversible LSD1 inhibitors.
Bioorg Chem. 2017 Jun;72:182-189. doi: 10.1016/j.bioorg.2017.04.006. Epub 2017 Apr 13.
8
Drug Design Concepts for LSD1-Selective Inhibitors.
Chem Rec. 2018 Dec;18(12):1782-1791. doi: 10.1002/tcr.201810031. Epub 2018 Sep 11.
9
Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors.
Bioorg Med Chem Lett. 2018 Jan 15;28(2):167-169. doi: 10.1016/j.bmcl.2017.11.035. Epub 2017 Nov 23.
10
Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A.
Eur J Med Chem. 2014 Oct 30;86:352-63. doi: 10.1016/j.ejmech.2014.08.068. Epub 2014 Aug 27.
引用本文的文献
1
Post-translational modifications in the pathophysiological process of metabolic dysfunction‑associated steatotic liver disease.
Cell Biosci. 2025 Jun 5;15(1):79. doi: 10.1186/s13578-025-01411-z.
2
Epigenetics in evolution and adaptation to environmental challenges: pathways for disease prevention and treatment.
Epigenomics. 2025 Apr;17(5):317-333. doi: 10.1080/17501911.2025.2464529. Epub 2025 Feb 13.
3
Targeting KDM1A in Neuroblastoma with NCL-1 Induces a Less Aggressive Phenotype and Suppresses Angiogenesis.
J Clin Med. 2024 Oct 12;13(20):6081. doi: 10.3390/jcm13206081.
4
Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates.
Biochemistry. 2024 Jun 4;63(11):1369-1375. doi: 10.1021/acs.biochem.4c00090. Epub 2024 May 14.
5
The Epigenetic Controller Lysine-Specific Demethylase 1 (LSD1) Regulates the Outcome of Hepatitis C Viral Infection.
Cells. 2023 Nov 3;12(21):2568. doi: 10.3390/cells12212568.
6
Long non-coding RNA in glioma: novel genetic players in temozolomide resistance.
Anim Cells Syst (Seoul). 2023 Feb 15;27(1):19-28. doi: 10.1080/19768354.2023.2175497. eCollection 2023.
7
Epigenetic Regulation of Breast Cancer Stem Cells Contributing to Carcinogenesis and Therapeutic Implications.
Int J Mol Sci. 2021 Jul 29;22(15):8113. doi: 10.3390/ijms22158113.
8
CRISPR/Cas: a Nobel Prize award-winning precise genome editing technology for gene therapy and crop improvement.
J Zhejiang Univ Sci B. 2021 Apr 15;22(4):253-284. doi: 10.1631/jzus.B2100009.
9
[Progress on epigenetic regulation of iron homeostasis].
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May 25;49(1):58-70. doi: 10.3785/j.issn.1008-9292.2020.02.25.
10
DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment.
Epigenetics. 2020 May;15(5):439-453. doi: 10.1080/15592294.2019.1699991. Epub 2019 Dec 28.
本文引用的文献
1
Medicinal chemistry insights in the discovery of novel LSD1 inhibitors.
Epigenomics. 2015;7(8):1379-96. doi: 10.2217/epi.15.86. Epub 2015 Dec 8.
2
Prognostic role of LSD1 in various cancers: evidence from a meta-analysis.
Onco Targets Ther. 2015 Sep 15;8:2565-70. doi: 10.2147/OTT.S89597. eCollection 2015.
3
LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control.
Nat Neurosci. 2015 Sep;18(9):1256-64. doi: 10.1038/nn.4069. Epub 2015 Jul 27.
4
A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC.
Cancer Cell. 2015 Jul 13;28(1):57-69. doi: 10.1016/j.ccell.2015.06.002.
5
Extranucleosomal DNA enhances the activity of the LSD1/CoREST histone demethylase complex.
Nucleic Acids Res. 2015 May 26;43(10):4868-80. doi: 10.1093/nar/gkv388. Epub 2015 Apr 27.
6
In vitro histone demethylase assays.
Methods Mol Biol. 2015;1288:109-22. doi: 10.1007/978-1-4939-2474-5_8.
7
Measurement of lysine-specific demethylase-1 activity in the nuclear extracts by flow-injection based time-of-flight mass spectrometry.
J Clin Biochem Nutr. 2015 Mar;56(2):123-31. doi: 10.3164/jcbn.14-99. Epub 2015 Feb 13.
8
A High-Throughput Mass Spectrometry Assay Coupled with Redox Activity Testing Reduces Artifacts and False Positives in Lysine Demethylase Screening.
J Biomol Screen. 2015 Jul;20(6):810-20. doi: 10.1177/1087057115575689. Epub 2015 Mar 9.
9
Interplay among nucleosomal DNA, histone tails, and corepressor CoREST underlies LSD1-mediated H3 demethylation.
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2752-7. doi: 10.1073/pnas.1419468112. Epub 2015 Feb 17.
10
Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures.
Bioorg Med Chem. 2015 Apr 1;23(7):1601-12. doi: 10.1016/j.bmc.2015.01.049. Epub 2015 Feb 7.
Zotero 插件