ML372
目录号 : GC64666ML372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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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 | DMSO : 33.33 mg/mL (92.47 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
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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.