DS79932728的发现：一种用于治疗β地中海贫血和镰状细胞病的强效口服G9a/GLP抑制剂。
Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease.
作者信息
Katayama Katsushi, Ishii Ken, Terashima Hideki, Tsuda Eisuke, Suzuki Makoto, Yotsumoto Keiichi, Hiramoto Kumiko, Yasumatsu Isao, Torihata Munefumi, Ishiyama Takashi, Muto Tsuyoshi, Katagiri Takahiro
机构信息
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
出版信息
ACS Med Chem Lett. 2020 Dec 28;12(1):121-128. doi: 10.1021/acsmedchemlett.0c00572. eCollection 2021 Jan 14.
Abstract
Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.
摘要
通过治疗性激活γ-珠蛋白基因来产生胎儿血红蛋白（HbF）是治疗β地中海贫血和镰状细胞病的一种有吸引力的策略。据报道，组蛋白赖氨酸甲基转移酶EHMT2/1（G9a/GLP）的基因敲低足以诱导HbF的产生。本研究的目的是获得一种能充分诱导HbF产生的G9a/GLP抑制剂。结果表明，四氢氮杂卓在各种骨架中作为侧链具有通用性。我们最终获得了一种有前景的氨基吲哚衍生物（DS79932728），一种强效且口服生物可利用的G9a/GLP抑制剂，该抑制剂在放血的食蟹猴模型中被发现可诱导γ-珠蛋白的产生。这项工作有助于开发治疗β地中海贫血和镰状细胞病的有效新方法。
相似文献
1
Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease.DS79932728的发现：一种用于治疗β地中海贫血和镰状细胞病的强效口服G9a/GLP抑制剂。
ACS Med Chem Lett. 2020 Dec 28;12(1):121-128. doi: 10.1021/acsmedchemlett.0c00572. eCollection 2021 Jan 14.
2
Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping.抑制G9a甲基转移酶可通过促进LCR/γ-珠蛋白环化来刺激胎儿血红蛋白的产生。
Blood. 2015 Jul 30;126(5):665-72. doi: 10.1182/blood-2015-02-629972. Epub 2015 May 15.
3
Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines.新型组蛋白赖氨酸甲基转移酶 G9a/GLP（EHMT2/1）抑制剂的发现：2,4-二氨基-6-甲基嘧啶的设计、合成及构效关系。
Bioorg Med Chem Lett. 2020 Oct 15;30(20):127475. doi: 10.1016/j.bmcl.2020.127475. Epub 2020 Aug 8.
4
EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression.EHMT1和EHMT2抑制可诱导胎儿血红蛋白表达。
Blood. 2015 Oct 15;126(16):1930-9. doi: 10.1182/blood-2015-06-649087. Epub 2015 Aug 28.
5
Thiourea derivatives induce fetal hemoglobin production in-vitro: A new class of potential therapeutic agents for β-thalassemia.硫脲衍生物在体外诱导胎儿血红蛋白生成：一类β-地中海贫血治疗的新潜在药物。
Eur J Pharmacol. 2019 Jul 15;855:285-293. doi: 10.1016/j.ejphar.2019.05.027. Epub 2019 May 14.
6
Tenofovir disoproxil fumarate induces fetal hemoglobin production in K562 cells and β-YAC transgenic mice: A therapeutic approach for γ-globin induction.富马酸替诺福韦二吡呋酯诱导 K562 细胞和 β-YAC 转基因小鼠产生胎儿血红蛋白：一种诱导 γ-珠蛋白的治疗方法。
Exp Cell Res. 2020 Sep 15;394(2):112168. doi: 10.1016/j.yexcr.2020.112168. Epub 2020 Jul 10.
7
Reactivation of Fetal Hemoglobin for Treating β-Thalassemia and Sickle Cell Disease.重新激活胎儿血红蛋白用于治疗β地中海贫血和镰状细胞病。
Adv Exp Med Biol. 2017;1013:177-202. doi: 10.1007/978-1-4939-7299-9_7.
8
Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia.表观遗传失活的 ERF 重新激活β-地中海贫血中的 γ-珠蛋白表达。
Am J Hum Genet. 2021 Apr 1;108(4):709-721. doi: 10.1016/j.ajhg.2021.03.005. Epub 2021 Mar 17.
9
Oral administration of the LSD1 inhibitor ORY-3001 increases fetal hemoglobin in sickle cell mice and baboons.口服LSD1抑制剂ORY-3001可增加镰状细胞病小鼠和狒狒的胎儿血红蛋白。
Exp Hematol. 2018 Nov;67:60-64.e2. doi: 10.1016/j.exphem.2018.08.003. Epub 2018 Aug 17.
10
Cilostazol-mediated reversion of γ-globin silencing is associated with a high level of HbF production: A potential therapeutic candidate for β-globin disorders.西洛他唑介导的γ-珠蛋白沉默逆转与高水平的 HbF 产生相关：β-珠蛋白疾病的潜在治疗候选药物。
Biomed Pharmacother. 2021 Oct;142:112058. doi: 10.1016/j.biopha.2021.112058. Epub 2021 Aug 23.
引用本文的文献
1
GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms.GLP和G9a组蛋白甲基转移酶作为淋巴样肿瘤的潜在治疗靶点。
Cancer Cell Int. 2024 Jul 12;24(1):243. doi: 10.1186/s12935-024-03441-y.
2
inactivation in pancreatic epithelial cells shapes the transcriptional landscape and inflammation response of the whole pancreas.胰腺上皮细胞中的失活塑造了整个胰腺的转录图谱和炎症反应。
Front Genet. 2024 Jun 14;15:1412767. doi: 10.3389/fgene.2024.1412767. eCollection 2024.
3
The Discovery of Selective Protein Arginine Methyltransferase 5 Inhibitors in the Management of β-Thalassemia through Computational Methods.通过计算方法在β-地中海贫血症的治疗中发现选择性蛋白质精氨酸甲基转移酶 5 抑制剂。
Molecules. 2024 Jun 4;29(11):2662. doi: 10.3390/molecules29112662.
4
In Silico Molecular Docking and Dynamics Simulation Analysis of Potential Histone Lysine Methyl Transferase Inhibitors for Managing β-Thalassemia.基于计算机的分子对接和动力学模拟分析用于治疗β-地中海贫血的潜在组蛋白赖氨酸甲基转移酶抑制剂。
Molecules. 2023 Oct 25;28(21):7266. doi: 10.3390/molecules28217266.
5
Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.发现首例 G9a/GLP 共价抑制剂。
J Med Chem. 2022 Aug 11;65(15):10506-10522. doi: 10.1021/acs.jmedchem.2c00652. Epub 2022 Jun 28.
6
Lysine methyltransferase inhibitors: where we are now.赖氨酸甲基转移酶抑制剂：我们目前的进展
RSC Chem Biol. 2021 Dec 13;3(4):359-406. doi: 10.1039/d1cb00196e. eCollection 2022 Apr 6.
7
Quinazoline Based HDAC Dual Inhibitors as Potential Anti-Cancer Agents.基于喹唑啉的 HDAC 双重抑制剂作为潜在的抗癌剂。
Molecules. 2022 Mar 31;27(7):2294. doi: 10.3390/molecules27072294.
8
Emerging role of G9a in cancer stemness and promises as a therapeutic target.G9a在癌症干性中的新作用及其作为治疗靶点的前景。
Oncogenesis. 2021 Nov 13;10(11):76. doi: 10.1038/s41389-021-00370-7.
本文引用的文献
1
Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines.新型组蛋白赖氨酸甲基转移酶 G9a/GLP（EHMT2/1）抑制剂的发现：2,4-二氨基-6-甲基嘧啶的设计、合成及构效关系。
Bioorg Med Chem Lett. 2020 Oct 15;30(20):127475. doi: 10.1016/j.bmcl.2020.127475. Epub 2020 Aug 8.
2
Design, synthesis, and optimization of a series of 2-azaspiro[3.3]heptane derivatives as orally bioavailable fetal hemoglobin inducers.一系列作为口服生物可利用胎儿血红蛋白诱导剂的2-氮杂螺[3.3]庚烷衍生物的设计、合成与优化。
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127425. doi: 10.1016/j.bmcl.2020.127425. Epub 2020 Jul 24.
3
Phenotypic-screening generates active novel fetal globin-inducers that downregulate Bcl11a in a monkey model.表型筛选产生了新型的活性胎儿珠蛋白诱导物，可在猴模型中下调 Bcl11a。
Biochem Pharmacol. 2020 Jan;171:113717. doi: 10.1016/j.bcp.2019.113717. Epub 2019 Nov 18.
4
Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents.组蛋白甲基转移酶（G9a）抑制剂作为抗癌药物的最新进展。
Eur J Med Chem. 2019 Oct 1;179:537-546. doi: 10.1016/j.ejmech.2019.06.072. Epub 2019 Jun 28.
5
Oral administration of the LSD1 inhibitor ORY-3001 increases fetal hemoglobin in sickle cell mice and baboons.口服LSD1抑制剂ORY-3001可增加镰状细胞病小鼠和狒狒的胎儿血红蛋白。
Exp Hematol. 2018 Nov;67:60-64.e2. doi: 10.1016/j.exphem.2018.08.003. Epub 2018 Aug 17.
6
Development and Characterization of a Model for Inducing Fetal Hemoglobin Production in Cynomolgus Macaques ().食蟹猕猴中诱导胎儿血红蛋白产生模型的建立与表征（）
Comp Med. 2018 Oct 1;68(5):396-402. doi: 10.30802/AALAS-CM-17-000124. Epub 2018 Aug 9.
7
Discovery of Reversible DNA Methyltransferase and Lysine Methyltransferase G9a Inhibitors with Antitumoral in Vivo Efficacy.发现具有抗肿瘤体内疗效的可逆 DNA 甲基转移酶和赖氨酸甲基转移酶 G9a 抑制剂。
J Med Chem. 2018 Aug 9;61(15):6518-6545. doi: 10.1021/acs.jmedchem.7b01926. Epub 2018 Jul 19.
8
Fetal haemoglobin induction in sickle cell disease.镰状细胞病中胎儿血红蛋白的诱导
Br J Haematol. 2018 Jan;180(2):189-200. doi: 10.1111/bjh.15021. Epub 2017 Nov 16.
9
Treating sickle cell disease by targeting HbS polymerization.通过靶向血红蛋白S聚合来治疗镰状细胞病。
Blood. 2017 May 18;129(20):2719-2726. doi: 10.1182/blood-2017-02-765891. Epub 2017 Apr 6.
10
The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis).LSD1抑制剂RN-1重现了狒狒（埃及狒狒）血红蛋白合成的胎儿模式。
Haematologica. 2016 Jun;101(6):688-97. doi: 10.3324/haematol.2015.140749. Epub 2016 Feb 8.
Zotero 插件