NMDI14
目录号 : GC32744
NMDI14是一种强效无义介导的mRNA降解（NMD）通路抑制剂。
Cas No.:307519-88-6
Sample solution is provided at 25 µL, 10mM.
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NMDI14 is potent inhibitor of nonsense mediated RNA decay (NMD)[1]. NMDI14 prevents the formation of the UPF1-SMG7 (or UPF1-SMG5) heterodimers, suppresses NMD and stabilizes W1282X mRNA [2]. NMDI14 has been widely used as a model compound to develop a series of derivatives and serve as anti-mesothelioma agents in vitro[3].
In vitro, NMDI14 treatment at 50μM for 6 hours significantly increased the expression level of p53 mRNA in U2OS cells, without affecting cell viability[4]. After treating primary nasal epithelial cells of W1282X heterozygous carriers with 5μM NMDI14 for 12 hours, the level of W1282X transcripts was significantly increased[5]. Treatment with 50 μM NMDI14 for 72 hours can prevent the upregulation of ABCC1 and ABCC2 mRNA mediated by human papilloma virus (HPV) 18 E6/E7 proteins in HNO206 cells[6]. 0.1μM of NMDI14 and CC-90009 (7.5nM) treatment for 2 days significantly promoted the increase in the expression of type XVII collagen in JEB-C17 keratinocytes without affecting cell viability[7].
In, vivo, NMDI14 treatment via intracerebroventricular injection (2μL; 674 μM) three times within 24h in a mouse model of status epilepticus significantly reduced the spontaneous epileptic seizures that occurred following the persistent state of epilepsy[8].
References:
[1] Evtushenko N, Beilin A, Novikov A, et al. 163 Nonsense-mediated mRNA decay inhibitors perspectives for recessive dystrophic epidermolysis bullosa treatment[J]. Journal of Investigative Dermatology, 2021, 141(10): S176.
[2] Ensinck M M, Carlon M S. One size does not fit all: the past, present and future of cystic fibrosis causal therapies[J]. Cells, 2022, 11(12): 1868.
[3] Nguyen H N, Suzuki K, Kimura Y, et al. Synthesis and biological evaluation of NMDI14 derivatives as anti-mesothelioma agents[J]. Heterocycles, 2020, 100(2): 253-266.
[4] Martin L, Grigoryan A, Wang D, et al. Identification and characterization of small molecules that inhibit nonsense-mediated RNA decay and suppress nonsense p53 mutations[J]. Cancer research, 2014, 74(11): 3104-3113.
[5] Aksit M A, Bowling A D, Evans T A, et al. Decreased mRNA and protein stability of W1282X limits response to modulator therapy[J]. Journal of Cystic Fibrosis, 2019, 18(5): 606-613.
[6] Rigalli J P, Reichel M, Tocchetti G N, et al. Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway[J]. Cancer letters, 2018, 428: 69-76.
[7] Sayar S B, Has C. Strategy for the optimization of read-through therapy for junctional epidermolysis bullosa with COL17A1 nonsense mutation[J]. Journal of Investigative Dermatology, 2024, 144(10): 2221-2229. e1.
[8] Mooney C M, Jimenez-Mateos E M, Engel T, et al. RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis[J]. Scientific reports, 2017, 7(1): 41517.
NMDI14是一种强效无义介导的mRNA降解（NMD）通路抑制剂[1]。NMDI14通过阻止UPF1-SMG7（或UPF1-SMG5）异源二聚体形成，抑制NMD过程并稳定W1282X mRNA[2]。NMDI14作为模型化合物被用于开发系列衍生物，并在体外研究中作为抗间皮瘤剂[3]。
在体外，50μM的NMDI14处理U2OS细胞6小时可显著提高p53 mRNA表达水平，且不影响细胞活力[4]。5μM的NMDI14处理W1282X杂合携带者的原代鼻上皮细胞12小时能显著增加W1282X转录本水平[5]。50μM的NMDI14处理HNO206细胞72小时可阻止人乳头瘤病毒（HPV）18 E6/E7蛋白介导的ABCC1和ABCC2 mRNA上调[6]。0.1μM的NMDI14与CC-90009（7.5nM）联合处理JEB-C17角质形成细胞2天能显著促进XVII型胶原表达，且不影响细胞活力[7]。
在体内，癫痫持续状态小鼠模型在24小时内三次脑室内注射NMDI14（2μl；674 μM）可显著减少癫痫持续状态后自发性癫痫发作[8]。
| Cell experiment [1]: | |
Cell lines | U2OS cells |
Preparation Method | U2OS cells were cultured in DMEM medium containing 10% fetal bovine serum. The cells were seeded in 6-well plates and after 24 hours, they were treated with NMDI14 (50μM) for 6 hours, and the expression of endogenous unmutated NMD targets was evaluated by real-time PCR. |
Reaction Conditions | 50μM; 6h |
Applications | NMDI14 treatment significantly enhanced the expression of p53 mRNA in U2OS cells. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6 mice |
Preparation Method | Anesthetize male C57BL/6 mice with isoflurane and place them in a stereotactic frame, which is equipped with cranial-mounted recording electrodes. Perform a craniotomy and place a guiding catheter above the right amygdala of the skull. Secure the components in place, then place the mouse in a warm recovery room. Next, using the catheter, microinject KA (0.3 μg; 0.2μl) into the right amygdala of the freely moving mouse. Seizures begin within 5-10 minutes and progressively worsen, becoming persistent epilepsy after approximately 30 minutes. 40 minutes after the KA seizure, administer lorazepam (8mg/kg; intraperitoneal injection) to reduce morbidity and mortality and limit the degree of hippocampal damage. Additional craniotomies were performed during the intracranial injection of the electrodes and guiding catheters. At 1, 4, and 24 hours after the lorazepam termination of the seizures, inject NMDI14 (2μl; 674 μM) into the ventricles, achieving a final ventricular NMDI14 concentration of approximately 50μM, for continuous video electroencephalogram monitoring of the mice. |
Dosage form | 2μl 674 μM three times a day for 1 day; i.c.v |
Applications | NMDI14 treatment reduced spontaneous epileptic seizures after status epilepticus in mice. |
References: | |
| Cas No. | 307519-88-6 | SDF | |
| Canonical SMILES | O=C(C1=C(NC(CC2NC3=C(C=C(C)C(C)=C3)NC2=O)=O)SC(C)=C1C)OCC | ||
| 分子式 | C21H25N3O4S | 分子量 | 415.51 |
| 溶解度 | DMSO : ≥ 25 mg/mL (60.17 mM) | 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 | 2.4067 mL | 12.0334 mL | 24.0668 mL |
| 5 mM | 481.3 μL | 2.4067 mL | 4.8134 mL |
| 10 mM | 240.7 μL | 1.2033 mL | 2.4067 mL |
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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 | ||||||||||
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工作液浓度： mg/ml；
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2.
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