EZM0414 (SETD2-IN-1) TFA
(Synonyms: SETD2-IN-1 TFA) 目录号 : GC62555
EZM0414 (SETD2-IN-1) TFA是EZM0414的三氟乙酸盐（TFA）形式。EZM0414 是一种首创的、强效的、选择性的、口服生物活性的小分子SETD2抑制剂，其IC50值为18nM。
Cas No.:2411759-92-5
Sample solution is provided at 25 µL, 10mM.
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EZM0414 (SETD2-IN-1) TFA is the TFA salt (Trifluoroacetate) form of EZM0414. EZM0414 is a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2 with an IC50 value of 18nM[1-2]. SETD2 is a member of the lysine N-methyltransferases (KMTs) and is the only known histone methyltransferase (HMT) capable of catalyzing the addition of the third methyl group to the dimethylated state of lysine 36 on histone H3 (H3K36me2). In addition to its role in histone methylation, SETD2 is involved in a variety of other cellular processes, including transcriptional elongation and regulation, alternative RNA splicing, DNA damage repair, and crosstalk with other histone modifications[3]. SETD2 was identified as a target of interest in multiple myeloma that features a t(4,14) translocation[2]. EZM0414 is used in the study of mutant lymphoma cells, neuropathic pain, and multiple myeloma [2, 4-5].
In vitro, inhibition of SETD2 by EZM0414 results in potent anti-proliferative effects in a panel of multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) cell lines. The median IC 50 value for EZM0414 in t(4;14) cell lines was 0.24µM as compared to 1.2µM for non-t(4;14) MM cell lines. Synergistic antiproliferative activity was also observed when EZM0414 was combined with certain standard of care agents for MM and DLBCL[2]. EZM0414 promoted the induction of epithelial-like colonies from human adult skin fibroblasts (hASFs) at 8-10 days, followed by the generation of hCiPSCs by greater than 8-fold. In addition, EZM0414 also promoted the induction of human somatic cells to pluripotent stem cells (hCiPSCs) from human adult adipose-derived stromal cells (hADSCs)[6].
In vivo, the mice were pretreated with EZM0414 (5mg/kg) intranasally 24h before the administration of lipopolysaccharide (LPS). Treatment with EZM0414 effectively alleviated LPS-induced pathological changes and reduced the infiltration of F4/80+ alveolar macrophages (AMs). The exposure of LPS resulted in increased bronchoalveolar lavage fluid (BALF) protein levels, which were attenuated by treatment with EZM0414. Furthermore, treatment with EZM0414 obviously attenuated the overexpression of Colony-sitmulating-factor (Csf2), Il-6, Il-1b, and Cxcl15 (IL-8 in human) in AMs[7].
References:
[1] John Lampe, et al. Substituted indoles and methods of use thereof. WO2020037079A1.
[2] Jennifer Totman, Dorothy Brach, Vinny Motwani, et al. Pharmacologic Inhibition of the Histone Methyltransferase SETD2 with EZM0414 As a Novel Therapeutic Strategy in Relapsed or Refractory Multiple Myeloma and Diffuse Large B-Cell Lymphoma. Blood 2021. 138 (Supplement 1): 1142.
[3] Alford JS, Lampe JW, Brach D, et al. Conformational-Design-Driven Discovery of EZM0414: A Selective, Potent SETD2 Inhibitor for Clinical Studies. ACS Med Chem Lett. 2022;13(7):1137-1143.
[4] Kwok HS, Freedy AM, Siegenfeld AP, et al. Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma. Nat Chem Biol. 2023;19(9):1105-1115.
[5] Chen G, Gu P, Wu W, et al. SETD2 deficiency in peripheral sensory neurons induces allodynia by promoting NMDA receptor expression through NFAT5 in rodent models. Int J Biol Macromol. 2024;282(Pt 5):136767.
[6] Liuyang S, Wang G, Wang Y, et al. Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming. Cell Stem Cell. 2023;30(4):450-459.e9.
[7] Zhu X, Xu B, Lian A, et al. Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis. Cell Rep. 2025;44(1):115219.
EZM0414 (SETD2-IN-1) TFA是EZM0414的三氟乙酸盐（TFA）形式。EZM0414 是一种首创的、强效的、选择性的、口服生物活性的小分子SETD2抑制剂，其IC50值为18nM[1-2]。SETD2是赖氨酸N-甲基转移酶（KMTs）的成员，是唯一已知的能够催化第三甲基加成到组蛋白H3上赖氨酸36的二甲基化状态（H3K36me2）的组蛋白甲基转移酶。除了在组蛋白甲基化中的作用外，SETD2还参与了多种其他细胞过程，包括转录延长和调控、选择性RNA剪接、DNA损伤修复以及与其他组蛋白修饰的相互作用[3]。SETD2 被确定为具有 t(4,14) 易位的多发性骨髓瘤的一个靶点[2]。EZM0414用于突变淋巴瘤细胞、神经性疼痛和多发性骨髓瘤的研究[2,4-5]。
在体外，通过EZM0414来抑制SETD2，对多发性骨髓瘤（MM）和弥漫性大B细胞淋巴瘤（DLBCL）细胞系表现出显著的抗增殖效果。在含有t(4;14)染色体易位的细胞系中，EZM0414的IC50中位数为0.24µM，与之相比，在非t(4;14)型MM细胞系中，IC50为1.2µM。当EZM0414与某些用于MM和DLBCL的标准治疗药物联合使用时，也观察到协同的抗增殖活性[2]。EZM0414在8-10天时显著促进了人类成年皮肤成纤维细胞（hASFs）中上皮样细胞集落的形成，并随后使人类有道多能干细胞（hCiPSC）的产生增加了8倍以上。此外，EZM0414还促进了人体细胞从人类成年脂肪来源的基质细胞（hADSCs）向多能干细胞（hCiPSCs）的诱导分化[6]。
在体内，在给予小鼠脂多糖（LPS）给药前24小时，用EZM0414（5mg/kg）鼻腔内对小鼠进行预处理。EZM0414的治疗可以有效缓解LPS诱导的病理变化，并减少F4/80+肺泡巨噬细胞（AMs）的浸润。LPS暴露导致支气管肺泡灌洗液（BALF）蛋白质水平升高，而经EZM0414治疗后，这一水平有所下降。此外，EZM0414治疗明显抑制了AMs中集落炎症因子（Csf2）、Il-6、Il-1b和Cxcl15（人Il-8）的过度表达[7]。
| Cell experiment [1]: | |
|
Cell lines |
hASFs and hADSCs |
|
Preparation Method |
For hCiPS cells induction, hADSCs/hASFs were seeded one day before stage I induction, in high-glucose DMEM supplemented with 15% FBS at a density of 1×104 cells per well of a 12-well plate or 0.5-0.6×104 cells per well of a 24-well plate. Then, the hADSCs culture medium was replaced with Stage I induction medium (containing EZM0414). Stage I induction medium. Knockout DMEM supplemented with 2% B27 supplement, 1% Knockout Serum Replacement (KSR), 1% GlutaMAX, 1% NEAA, 1% Penicillin-Streptomycin, 50μg/ml Vc2p, 5mM LiCl, 1mM Nicotinamide (NAM), 20ng/mL BMP4, and the small molecules CHIR999021 (5μM), 616452 (10μM), TTNPB (2μM), SAG (0.5μM), EPZ5676 (2μM), DZNep (0.05μM), Ruxolitinib (1μM), VTP50469 (0.5μM), AKT Kinase Inhibitor (1μM), JNKIN8 (0.2μM), and EZM0414 (0.2μM). |
|
Reaction Conditions |
0.2μM; 8-10 day |
|
Applications |
EZM0414 promoted the induction of epithelial-like colonies from hASFs at stage I, followed by the generation of hCiPSCs by greater than 8-fold. In addition, EZM0414 also promoted the induction of hCiPSCs from hADSCs. |
| Animal experiment [2]: | |
|
Animal models |
6-to 8-week-old C57BL/6J mice |
|
Preparation Method |
The acute lung injury model (ALI) was induced by injecting 6- to 8-week-old C57BL/6J mice with lipopolysaccharide (LPS) at a dose of 5mg/kg. Therapeutically, the mice were pretreated with EZM0414 (5mg/kg) intranasally 24h before the administration of LPS. After 24h, the pathological alterations in lung tissues were examined, and the changes in the mRNA expression levels of inflammatory factors in AMs, as well as the protein levels in BALF, were detected. |
|
Dosage form |
5mg/kg; intranasally |
|
Applications |
Treatment with EZM0414 effectively alleviated LPS-induced pathological changes and reduced the infiltration of F4/80+ AMs. The exposure of LPS resulted in increased BALF protein levels, which were attenuated by treatment with EZM0414. Furthermore, treatment with EZM0414 obviously attenuated the overexpression of Colony-sitmulating-factor (Csf2), Il-6, Il-1b, and Cxcl15 (IL-8 in human) in AMs. |
|
References: |
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| Cas No. | 2411759-92-5 | SDF | |
| 别名 | SETD2-IN-1 TFA | ||
| 分子式 | C24H30F4N4O4 | 分子量 | 514.51 |
| 溶解度 | DMSO : 200 mg/mL (388.72 mM; Need ultrasonic) | 储存条件 | 4°C, sealed storage, away from moisture |
| 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9436 mL | 9.718 mL | 19.436 mL |
| 5 mM | 0.3887 mL | 1.9436 mL | 3.8872 mL |
| 10 mM | 0.1944 mL | 0.9718 mL | 1.9436 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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