组蛋白赖氨酸去甲基化酶抑制剂。
Histone Lysine Demethylase Inhibitors.
机构信息
Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
出版信息
Cold Spring Harb Perspect Med. 2017 Jan 3;7(1):a026484. doi: 10.1101/cshperspect.a026484.
Abstract
The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors. This review will briefly outline the connection between demethylases and cancer and will provide a comprehensive overview of the structure, specificity, and utility of currently available demethylase inhibitors. To date, a select group of demethylase inhibitors is being evaluated in clinical trials, and additional compounds may soon follow from the bench to the bedside.
摘要
组蛋白共价修饰的动态调控对于维持基因组完整性和细胞身份至关重要，而这种调控在癌症中经常受到破坏。许多类型的血液和实体肿瘤中都有组蛋白赖氨酸去甲基酶的异常表达，因此去甲基酶是很有前途的治疗靶点。高通量化学筛选、基于结构的药物设计和结构活性关系研究的最新进展提高了去甲基酶抑制剂的特异性和体内疗效。这篇综述将简要概述去甲基酶与癌症之间的联系，并全面概述目前可用的去甲基酶抑制剂的结构、特异性和用途。迄今为止，已有一组选择性的去甲基酶抑制剂正在临床试验中进行评估，并且可能很快会有更多的化合物从实验室走向临床。
相似文献
1
Histone Lysine Demethylase Inhibitors.组蛋白赖氨酸去甲基化酶抑制剂。
Cold Spring Harb Perspect Med. 2017 Jan 3;7(1):a026484. doi: 10.1101/cshperspect.a026484.
2
The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors.组蛋白甲基转移酶和去甲基酶抑制剂新出现的治疗潜力。
ChemMedChem. 2009 Oct;4(10):1568-82. doi: 10.1002/cmdc.200900301.
3
Inhibitors of enzymes catalyzing modifications to histone lysine residues: structure, function and activity.催化组蛋白赖氨酸残基修饰的酶的抑制剂：结构、功能与活性
Future Med Chem. 2016 May;8(8):879-97. doi: 10.4155/fmc-2016-0021. Epub 2016 May 13.
4
Targeting histone lysine methylation in cancer.靶向癌症中的组蛋白赖氨酸甲基化。
Pharmacol Ther. 2015 Jun;150:1-22. doi: 10.1016/j.pharmthera.2015.01.002. Epub 2015 Jan 9.
5
The role of histone demethylases in cancer therapy.组蛋白去甲基化酶在癌症治疗中的作用。
Mol Oncol. 2012 Dec;6(6):683-703. doi: 10.1016/j.molonc.2012.07.004. Epub 2012 Aug 7.
6
The future therapeutic potential of histone demethylases: A critical analysis.组蛋白去甲基化酶的未来治疗潜力：批判性分析
Curr Opin Drug Discov Devel. 2009 Sep;12(5):607-15.
7
A comprehensive review of lysine-specific demethylase 1 and its roles in cancer.赖氨酸特异性去甲基化酶1及其在癌症中的作用的全面综述。
Epigenomics. 2017 Aug;9(8):1123-1142. doi: 10.2217/epi-2017-0022. Epub 2017 Jul 12.
8
Identification of selective and reversible LSD1 inhibitors with anti-metastasis activity by high-throughput docking.通过高通量对接鉴定具有抗转移活性的选择性和可逆 LSD1 抑制剂。
Bioorg Med Chem Lett. 2019 Feb 15;29(4):544-548. doi: 10.1016/j.bmcl.2018.12.067. Epub 2019 Jan 2.
9
Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy.在癌症治疗临床试验中靶向组蛋白甲基转移酶和去甲基酶。
Clin Epigenetics. 2016 May 24;8:57. doi: 10.1186/s13148-016-0223-4. eCollection 2016.
10
Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors.包含修饰赖氨酸残基的组蛋白H3肽作为赖氨酸特异性去甲基化酶1抑制剂。
Bioorg Med Chem Lett. 2018 Jan 15;28(2):167-169. doi: 10.1016/j.bmcl.2017.11.035. Epub 2017 Nov 23.
引用本文的文献
1
Hypoxia-induced genome-wide DNA demethylation by DNMT3A and EMT of cancer cells.缺氧通过DNMT3A诱导全基因组DNA去甲基化及癌细胞上皮-间质转化。
Cell Mol Biol Lett. 2025 Aug 5;30(1):95. doi: 10.1186/s11658-025-00775-x.
2
LSD1 is a targetable vulnerability in gastric cancer harboring TP53 frameshift mutations.赖氨酸特异性去甲基化酶1（LSD1）是携带TP53移码突变的胃癌中一个可靶向治疗的薄弱环节。
Clin Epigenetics. 2025 Feb 18;17(1):26. doi: 10.1186/s13148-025-01829-9.
3
A Live-Cell Epigenome Manipulation by Photo-Stimuli-Responsive Histone Methyltransferase Inhibitor.光响应组蛋白甲基转移酶抑制剂的活细胞表观基因组操作。
Adv Sci (Weinh). 2024 Nov;11(41):e2404608. doi: 10.1002/advs.202404608. Epub 2024 Sep 9.
4
Cyclic peptides target the aromatic cage of a PHD-finger reader domain to modulate epigenetic protein function.环肽靶向PHD指蛋白阅读器结构域的芳香笼以调节表观遗传蛋白功能。
Chem Sci. 2023 Apr 17;14(26):7136-7146. doi: 10.1039/d2sc05944d. eCollection 2023 Jul 5.
5
Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy.DNA胞嘧啶修饰的表观遗传调控因子：癌症治疗的潜在靶点
Biomedicines. 2023 Feb 21;11(3):654. doi: 10.3390/biomedicines11030654.
6
Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery.靶向组蛋白赖氨酸去甲基化酶家族的化学抑制剂及其药物研发潜力
Epigenomes. 2023 Mar 11;7(1):7. doi: 10.3390/epigenomes7010007.
7
Colitis Induces Sex-Specific Intestinal Transcriptomic Responses in Mice.结肠炎在雌雄小鼠肠道中诱导出具有性别特异性的转录组反应。
Int J Mol Sci. 2022 Sep 8;23(18):10408. doi: 10.3390/ijms231810408.
8
LSD1 regulates the FOXF2-mediated Wnt/β-catenin signaling pathway by interacting with Ku80 to promote colon cancer progression.赖氨酸特异性去甲基化酶1（LSD1）通过与Ku80相互作用来调节FOXF2介导的Wnt/β-连环蛋白信号通路，从而促进结肠癌进展。
Am J Cancer Res. 2022 Aug 15;12(8):3693-3712. eCollection 2022.
9
Histone Demethylase JMJD2D: A Novel Player in Colorectal and Hepatocellular Cancers.组蛋白去甲基化酶JMJD2D：结直肠癌和肝细胞癌中的新角色
Cancers (Basel). 2022 Jun 8;14(12):2841. doi: 10.3390/cancers14122841.
10
The Influence of Arginine Methylation in Immunity and Inflammation.精氨酸甲基化在免疫和炎症中的影响。
J Inflamm Res. 2022 May 13;15:2939-2958. doi: 10.2147/JIR.S364190. eCollection 2022.
本文引用的文献
1
Synthesis and biological evaluation of novel (E)-N'-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors.新型（E）-N'-（2,3-二氢-1H-茚-1-亚基）苯甲酰肼作为强效LSD1抑制剂的合成及生物学评价
Bioorg Med Chem Lett. 2016 Sep 15;26(18):4552-4557. doi: 10.1016/j.bmcl.2015.06.054. Epub 2015 Jun 20.
2
UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.UTX 抑制作为针对 TAL1 驱动的 T 细胞急性淋巴细胞白血病的选择性表观遗传治疗。
Genes Dev. 2016 Mar 1;30(5):508-21. doi: 10.1101/gad.276790.115.
3
The histone demethylase LSD1 is a novel oncogene and therapeutic target in oral cancer.组蛋白去甲基化酶 LSD1 是口腔癌中的一个新的癌基因和治疗靶点。
Cancer Lett. 2016 Apr 28;374(1):12-21. doi: 10.1016/j.canlet.2016.02.004. Epub 2016 Feb 9.
4
Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.发现一种新型组蛋白赖氨酸特异性去甲基化酶1A（KDM1A/LSD1）抑制剂作为口服活性抗肿瘤药物。
J Med Chem. 2016 Feb 25;59(4):1501-17. doi: 10.1021/acs.jmedchem.5b01209. Epub 2016 Jan 7.
5
Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.片段对接与连接以发现 Jumonji 组蛋白去甲基化酶抑制剂
J Med Chem. 2016 Feb 25;59(4):1580-98. doi: 10.1021/acs.jmedchem.5b01527. Epub 2015 Dec 23.
6
5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.5-羧基-8-羟基喹啉是一种导致铁转运的广谱2-氧代戊二酸加氧酶抑制剂。
Chem Sci. 2013 Aug 1;4(8):3110-3117. doi: 10.1039/C3SC51122G.
7
Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor.一种基于三唑并吡啶的组蛋白去甲基化酶抑制剂的优化产生了一种强效且选择性的KDM2A（FBXL11）抑制剂。
Medchemcomm. 2014 Dec 1;5(12):1879-1886. doi: 10.1039/C4MD00291A.
8
3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1.含3-(哌啶-4-基甲氧基)吡啶的化合物是赖氨酸特异性去甲基化酶1的强效抑制剂。
J Med Chem. 2016 Jan 14;59(1):253-263. doi: 10.1021/acs.jmedchem.5b01361. Epub 2015 Dec 24.
9
Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases.组蛋白H3赖氨酸4去甲基化酶KDM5/JARID1家族的一个相连的Jumonji结构域的表征
J Biol Chem. 2016 Feb 5;291(6):2631-46. doi: 10.1074/jbc.M115.698449. Epub 2015 Dec 8.
10
GSKJ4, A Selective Jumonji H3K27 Demethylase Inhibitor, Effectively Targets Ovarian Cancer Stem Cells.GSKJ4，一种选择性的Jumonji H3K27去甲基化酶抑制剂，可有效靶向卵巢癌干细胞。
Anticancer Res. 2015 Dec;35(12):6607-14.
Zotero 插件