MS023
(Synonyms: N1-甲基-N1-[[4-[4-(异丙氧基)苯基]-1H-吡咯-3-基]甲基]-1,2-乙二胺) 目录号 : GC10099
An inhibitor of type I PRMTs
Cas No.:1831110-54-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Two human colon carcinoma cell lines DLD1 and HCT116 |
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Preparation Method |
CRC cells were seeded into 96-well plates at a density of 5 × 103 cells in 100 µl medium per well and cultured in 5% humidified atmosphere at 37 °C. After 24 h incubation, MS023 alone or combined with SN-38 was treated with increasing concentrations for 2 days. |
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Reaction Conditions |
0-200µM for 2 days |
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Applications |
Concentration of MS023 (125 µM) which resulted in about 40% reduction of CRC cell growth, MS023 significantly enhanced SN-38 cytotoxicity in DLD1 and HCT116 cells. |
| Animal experiment [2]: | |
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Animal models |
Severe combined immunodeficient mice |
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Preparation Method |
7 × 106 MDA-MB-468 cells were injected into the mice, MS023 was prepared at 5% N-Methyl-2-pyrrolidone (NMP), 20% captisol (wt/vol), 20% PEG-400 and 55% normal saline and administered to the mice by intraperitoneal injection. Tumors grown to a detectable size, as assessed by palpation (~2 mm in diameter), and started to treat with 60 mg kg–1 MS023 daily for a total of 5 weeks. |
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Dosage form |
Intraperitoneal injection, 60 mg kg-1d-1 for 5 weeks. |
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Applications |
Once-daily dosing of 60 mg kg-1 MS023 initiated in mice with palpable tumors significantly reduced tumor growth and final tumor weight. |
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References: [1]: Lim Y, Lee J Y, Ha S J, et al. Proteome-wide identification of arginine methylation in colorectal cancer tissues from patients[J]. Proteome Science, 2020, 18(1): 1-11. |
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MS023 is a potent, selective, and cell-active inhibitor of type I protein arginine methyltransferases (PRMTs) [1]. with IC50s of 30, 119, 83, 4 and 5 nM for PRMT1, PRMT3, PRMT4, PRMT6, and PRMT8, respectively [1].
MS023 treatment (48 h exposure) potently and concentration dependently reduced cellular levels of H4R3me2a (IC50 = 9 ± 0.2 nM), PRMT1 is the main contributor to H4R3 (histone H4 arginine 3) asymmetric dimethylation (H4R3me2a) in cells. MS023 (20 h exposure) concentration dependently reduced the H3R2me2a mark in HEK293 cells (IC50 = 56 ± 7 nM), PRMT6 robustly increased endogenous asymmetric dimethylation of H3R2 (histone H3 arginine 2) [1]. MS023 (1μM, 24h) significantly reduced SARS-CoV-2 replication in VeroE6 cells by inhibition of arginine methylation [2]. MS023 (150,175,200μM) for 48 h treated DLD1 and HCT116 cells increased levels of active form of caspase 3 and PARP degradation as representative apoptosis-related proteins [3].
MS023 treatment on mice model of spinal muscular atrophy (SMA) with both 2 mg/kg and 5 mg/kg resulted in significant increase in survival, with the 2 mg/kg dose achieving the best effect (median: 10 days), compared to both untreated (median: 7) and vehicle-treated (median: 6 days) mice. Mice treated with MS023 also showed an improvement in the disease-associated weight loss [4]. Once-daily dosing of 60 mg kg-1 MS023 initiated in mice with palpable tumors significantly reduced tumor growth and final tumor weight on MDA-MB-468 xenograft mice [5].
References:
[1]. Eram M S, Shen Y, Szewczyk M M, et al. A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases[J]. ACS chemical biology, 2016, 11(3): 772-781.
[2]. Cai T, Yu Z, Wang Z, et al. Arginine methylation of SARS-Cov-2 nucleocapsid protein regulates RNA binding, its ability to suppress stress granule formation, and viral replication[J]. Journal of Biological Chemistry, 2021, 297(1).
[3]. Lim Y, Lee J Y, Ha S J, et al. Proteome-wide identification of arginine methylation in colorectal cancer tissues from patients[J]. Proteome Science, 2020, 18(1): 1-11.
[4]. Kordala A J, Ahlskog N, Hanifi M, et al. Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice[J]. bioRxiv, 2022.
[5]. Wu Q, Nie D Y, Ba-Alawi W, et al. PRMT inhibition induces a viral mimicry response in triple-negative breast cancer[J]. Nature Chemical Biology, 2022: 1-10.
MS023 是 I 型蛋白精氨酸甲基转移酶 (PRMT) 的有效、选择性和细胞活性抑制剂[1]。 PRMT1、PRMT3、PRMT4、PRMT6 和 PRMT8 的 IC50 分别为 30、119、83、4 和 5 nM [1]。
MS023 处理（暴露 48 小时）有效且浓度依赖性地降低 H4R3me2a 的细胞水平（IC50 = 9 ± 0.2 nM），PRMT1 是细胞中 H4R3（组蛋白 H4 精氨酸 3）不对称二甲基化 (H4R3me2a) 的主要贡献者。 MS023（暴露 20 小时）浓度依赖性降低 HEK293 细胞中的 H3R2me2a 标记（IC50 = 56 ± 7 nM），PRMT6 显着增加 H3R2（组蛋白 H3 精氨酸 2）的内源性不对称二甲基化 [1]。 MS023（1μM，24 小时）通过抑制精氨酸甲基化显着降低 SARS-CoV-2 在 VeroE6 细胞中的复制 [2]。 MS023 (150,175,200μM) 处理 DLD1 和 HCT116 细胞 48 小时后，作为代表性的细胞凋亡相关蛋白 [3]，可增加 caspase 3 活性形式和 PARP 降解的水平。
MS023 以 2 mg/kg 和 5 mg/kg 的剂量处理脊髓性肌萎缩症 (SMA) 小鼠模型可显着提高存活率，其中 2 mg/kg 的剂量达到最佳效果（中位数:10 天） ，与未处理（中位数:7）和载体处理（中位数:6 天）的小鼠相比。接受 MS023 治疗的小鼠在与疾病相关的体重减轻方面也有所改善[4]。在 MDA-MB-468 异种移植小鼠上，每天一次给予 60 mg kg-1 MS023 可显着降低肿瘤生长和最终肿瘤重量[5]。
| Cas No. | 1831110-54-3 | SDF | |
| 别名 | N1-甲基-N1-[[4-[4-(异丙氧基)苯基]-1H-吡咯-3-基]甲基]-1,2-乙二胺 | ||
| 化学名 | N1-((4-(4-isopropoxyphenyl)-1H-pyrrol-3-yl)methyl)-N1-methylethane-1,2-diamine | ||
| Canonical SMILES | NCCN(C)CC1=CNC=C1C2=CC=C(OC(C)C)C=C2 | ||
| 分子式 | C17H25N3O | 分子量 | 287.4 |
| 溶解度 | ≥ 28.7mg/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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| 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 | 3.4795 mL | 17.3974 mL | 34.7947 mL |
| 5 mM | 0.6959 mL | 3.4795 mL | 6.9589 mL |
| 10 mM | 0.3479 mL | 1.7397 mL | 3.4795 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PRMT inhibition induces a viral mimicry response in triple-negative breast cancer
Nat Chem Biol2022 Aug;18(8):821-830.PMID: 35578032DOI: 10.1038/s41589-022-01024-4
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.
PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia
Blood2019 Aug 8;134(6):548-560.PMID: 31217189DOI: 10.1182/blood.2019001282
The presence of FMS-like receptor tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate primitive FLT3-ITD+ leukemia cells, which are potential sources of relapse. Thus, understanding the mechanisms underlying FLT3-ITD+ AML cell persistence is essential to devise future AML therapies. Here, we show that expression of protein arginine methyltransferase 1 (PRMT1), the primary type I arginine methyltransferase, is increased significantly in AML cells relative to normal hematopoietic cells. Genome-wide analysis, coimmunoprecipitation assay, and PRMT1-knockout mouse studies indicate that PRMT1 preferentially cooperates with FLT3-ITD, contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD+ AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginine 972/973, and PRMT1 promoted leukemia cell growth in an FLT3 methylation-dependent manner. Moreover, the effects of FLT3-ITD methylation in AML cells were partially due to cross talk with FLT3-ITD phosphorylation at tyrosine 969. Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following kinase inhibition, indicating that methylation occurs independently of kinase activity. Finally, in patient-derived xenograft and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML cells relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes AML maintenance and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to eliminate FLT3-ITD+ AML cells.