Biological Activity:
NVS-SM1 is a highly potent, selective and orally active small molecule SMN2 splicing modulator enhancing SMN exon 7 inclusion with EC50 ~20 nM. It elevates full-length SMN protein and extends survival in a severe Spinal Muscular Atrophy (SMA) mouse model. The molecular mechanism of action for NVS-SM1 is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases. Currently NVS-SM1 is in phase I clinical trial for treatment of type I SMA
How to Use:
In vitro: NVS-SM1 was used at 0.1-1 µM final concentration in vitro and in cellular assays.
In vivo: NVS-SM1 was dose to C/+ SMA mouse model by oral administration at 1-3 mg/kg once per day.
References:
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