ML372
目录号 : GC64666
ML372可抑制生存运动神经元 (SMN) 蛋白泛素化，增加 SMN 蛋白稳定性而不影响 mRNA 表达。ML372 可改善小鼠脊髓性肌萎缩症 (SMA)。ML372 具有脑渗透性，在体内具有合理的暴露量和半衰期。
Cas No.:1331745-61-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
ML372 inhibits survival motor neuron (SMN) protein ubiquitination, increases SMN protein stability without affecting mRNA expression. ML372 improves spinal muscular atrophy (SMA) in mice. ML372 is brain penetrant and has a reasonable exposure and half-life in vivo[1].
[1]. Mahlet B Abera, et al. ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice. JCI Insight. 2016 Nov 17;1(19):e88427.
| Cas No. | 1331745-61-9 | SDF | Download SDF |
| 分子式 | C18H20N2O4S | 分子量 | 360.43 |
| 溶解度 | 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 | 2.7745 mL | 13.8723 mL | 27.7446 mL |
| 5 mM | 0.5549 mL | 2.7745 mL | 5.5489 mL |
| 10 mM | 0.2774 mL | 1.3872 mL | 2.7745 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。
ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice
JCI Insight 2016 Nov 17;1(19):e88427.PMID:27882347DOI:10.1172/jci.insight.88427.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient-derived cells. We show here that ML372, a representative of this series, almost doubles the half-life of residual SMN protein expressed from the SMN2 locus by blocking its ubiquitination and subsequent degradation by the proteasome. ML372 increased SMN protein levels in muscle, spinal cord, and brain tissue of SMA mice. Importantly, ML372 treatment improved the righting reflex and extended survival of a severe mouse model of SMA. These results demonstrate that slowing SMN degradation by selectively inhibiting its ubiquitination can improve the motor phenotype and lifespan of SMA model mice.
A combinatorial approach increases SMN level in SMA model mice
Hum Mol Genet 2022 Aug 25;31(17):2989-3000.PMID:35419606DOI:10.1093/hmg/ddac068.
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced expression of the survival motor neuron (SMN) protein. Current disease-modifying therapies increase SMN levels and dramatically improve survival and motor function of SMA patients. Nevertheless, current treatments are not cures and autopsy data suggest that SMN induction is variable. Our group and others have shown that combinatorial approaches that target different modalities can improve outcomes in rodent models of SMA. Here we explore if slowing SMN protein degradation and correcting SMN splicing defects could synergistically increase SMN production and improve the SMA phenotype in model mice. We show that co-administering ML372, which inhibits SMN ubiquitination, with an SMN-modifying antisense oligonucleotide (ASO) increases SMN production in SMA cells and model mice. In addition, we observed improved spinal cord, neuromuscular junction and muscle pathology when ML372 and the ASO were administered in combination. Importantly, the combinatorial approach resulted in increased motor function and extended survival of SMA mice. Our results demonstrate that a combination of treatment modalities synergistically increases SMN levels and improves pathophysiology of SMA model mice over individual treatment.