A 366是一种选择性的G9a/GLP组蛋白甲基转移酶抑制剂，可抑制G9a（IC50=3.3nM）和GLP（IC50=38nM）的活性。
Cas No.:1527503-11-2
Sample solution is provided at 25 µL, 10mM.
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A 366 is a selective G9a/GLP histone methyltransferase inhibitor that inhibits the activity of G9a (IC50=3.3nM) and GLP (IC50=38nM). A 366 suppresses H3K9me2 methylation and interferes with the binding of Spindlin1 to H3K4me3[1-2]. A 366 can be used in research related to leukemia, prostate cancer, and autism spectrum disorders[3-4].
In vitro, U2OS human osteosarcoma cells were treated with A 366 (10μM) in combination with phleomycin (0.5–1μM) or etoposide (100nM) for 0-180 minutes. A 366 significantly impaired DNA double-strand break repair, enhanced DNA damage accumulation, and synergistically induced tumor cell death[5]. Human monocytes, M1/M2 monocyte-derived macrophages, CD4+ T cells, and B cells were pretreated with A 366 (5–50μM) for 30 minutes, followed by incubation with different inducters for 24 hours to 5 days. A 366 attenuated the M2 polarization of macrophages; A 366 also significantly inhibited the proliferation of B cells, the formation of plasmablasts, and the release of immunoglobulins G and A[6].
In vivo, Balb/c nu/nu mice bearing OPM2 multiple myeloma xenografts were treated with A 366 alone (8mg/kg; i.p.; for 6 days) or in combination with decitabine (0.2mg/kg) for the final 3 days. A 366 significantly inhibited tumor growth in the xenograft model, and the combination therapy demonstrated a synergistic antitumor effect without causing significant toxicity[7]. Wistar rats were treated with A 366 (25mg/kg; a single intraperitoneal injection). A 366 significantly reduced the clonogenic capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs), prolonged their population doubling time, increased their adipogenic differentiation potential, and decreased their osteogenic differentiation potential[8].
References:
[1] Reiner D, Seifert L, Deck C, et al. Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H3 receptor for Prader-Willi Syndrome. Sci Rep. 2020 Aug 11;10(1):13558.
[2] Wagner T, Greschik H, Burgahn T, et al. Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res. 2016 May 19;44(9):e88.
[3] Sweis RF, Pliushchev M, Brown PJ, et al. Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett. 2014 Jan 2;5(2):205-9.
[4] Pappano WN, Guo J, He Y, et al. The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia. PLoS One. 2015 Jul 6;10(7):e0131716.
[5] Agarwal P, Jackson SP. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status. Cancer Lett. 2016 Oct 1;380(2):467-475.
[6] Schiffmann S, Henke M, Weber F, et al. Immune-modulatory effects of Spindlin-1 inhibitors. Clin Exp Immunol. 2025 Jan 21;219(1):uxaf013.
[7] Nylund P, Garrido-Zabala B, Tziola SI, et al. Dual targeting of G9a and DNMTs induces antitumor effects in multiple myeloma. Blood Adv. 2025 Oct 14;9(19):4825-4841.
[8] Khanban H, Fattahi E, Talkhabi M. In vivo administration of G9a inhibitor A366 decreases osteogenic potential of bone marrow-derived mesenchymal stem cells. EXCLI J. 2019 Jun 3;18:300-309.
A 366是一种选择性的G9a/GLP组蛋白甲基转移酶抑制剂，可抑制G9a（IC50=3.3nM）和GLP（IC50=38nM）的活性。A 366可抑制H3K9me2甲基化并干扰Spindlin1与H3K4me3的结合[1-2]。A 366可用于白血病、前列腺癌和自闭症谱系障碍的相关研究[3-4]。
在体外，A 366（10μM）联合phleomycin（0.5–1μM）或etoposide（100nM）处理人骨肉瘤U2OS细胞0-180分钟。A 366显著损害DNA双链断裂修复，增强DNA损伤积累，并协同诱导肿瘤细胞死亡[5]。A 366（5–50μM）处理预处理人单核细胞、M1/M2型单核来源巨噬细胞、CD4+ T细胞及B细胞30分钟后，加入不同的诱导剂孵育细胞24小时至5天。A 366可减弱巨噬细胞的M2极化；A 366可显著抑制B细胞的增殖、浆母细胞形成以及免疫球蛋白G和A的释放[6]。
在体内，A 366（8mg/kg；腹腔注射；持续6天）单独处理携带OPM2多发骨髓瘤细胞的Balb/c nu/nu小鼠，或再联合decitabine（0.2mg/kg）处理3天。A 366在异种移植模型中显著抑制了肿瘤生长，联合疗法显示出协同抗肿瘤效应，且未引起明显毒性反应[7]。A 366（25mg/kg；单次腹腔注射）处理Wistar大鼠。A 366显著降低了骨髓间充质干细胞（BM-MSCs）的克隆形成能力，延长了BM-MSCs倍增时间，同时增加了BM-MSCs成脂分化潜能并降低了成骨分化潜能[8]。
| Cell experiment [1]: | |
Cell lines | U2OS cells (human osteosarcoma cell line) and HCT116 cells (human colorectal carcinoma cell line, both p53 wild-type and p53 knockout variants) |
Preparation Method | Cells were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) at 37°C under 5% CO₂. For testing, U2OS cells were treated with A 366 (10μM) in combination with the DNA double-strand break (DSB) inducing agents phleomycin or etoposide. |
Reaction Conditions | 10μM; 0-180min. |
Applications | A 366 significantly potentiated the anti-tumour activity of DSB-inducing agents. A 366 hypersensitized U2OS tumor cells to low doses of phleomycin or etoposide, impairing DSB repair and leading to increased accumulation of DNA damage markers (γH2AX and 53BP1 foci) and ultimately tumor cell death. This effect was independent of p53 status. |
| Animal experiment [2]: | |
Animal models | Balb/c nu/nu mice bearing subcutaneous OPM2 multiple myeloma xenografts |
Preparation Method | Female immunodeficient mice were inoculated with OPM2 cells. For monotherapy, mice were treated with A366 via intraperitoneal injection daily for 9 days. For combination therapy, mice were treated with A 366 (8mg/kg) daily for 6 days, with the DNMT inhibitor decitabine co-administered during the final 72 hours. |
Dosage form | 8mg/kg; i.p.; daily for 6-9 days. |
Applications | A 366 monotherapy significantly inhibited tumor growth in vivo and demonstrated on-target activity by reducing global H3K9me2 levels in tumors. The combination of A 366 and decitabine resulted in a synergistic antitumor effect, leading to robust tumor regression superior to either agent alone, and was well-tolerated without significant toxicity. |
References: | |
| Cas No. | 1527503-11-2 | SDF | |
| 化学名 | 5'-methoxy-6'-(3-(pyrrolidin-1-yl)propoxy)spiro[cyclobutane-1,3'-indol]-2'-amine | ||
| Canonical SMILES | NC1=NC2=CC(OCCCN3CCCC3)=C(OC)C=C2C14CCC4 | ||
| 分子式 | C19H27N3O2 | 分子量 | 329.44 |
| 溶解度 | ≥ 11.9mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.0355 mL | 15.1773 mL | 30.3545 mL |
| 5 mM | 607.1 μL | 3.0355 mL | 6.0709 mL |
| 10 mM | 303.5 μL | 1.5177 mL | 3.0355 mL |
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