Background
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].
参考文献:
[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]。
Protocol
| Cell experiment [1]: |
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Cell lines
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Two human colon carcinoma cell lines DLD1 and HCT116
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Preparation Method
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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
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0-200μM for 2 days
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Applications
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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.
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| Animal experiment [2]: |
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Animal models
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Severe combined immunodeficient mice
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Preparation Method
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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
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Intraperitoneal injection, 60 mg kg-1d-1 for 5 weeks.
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Applications
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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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参考文献:
[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.
[2]: 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.
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