ML104 : SMN2 (Survival Motor Neuron 2) Modulator
ML104
Target Name
Survival Motor Neuron 2
Target Alias
SMN2
Target Class
RNA Splicing Factor
Mechanism of Action
Modulator of SMN2
Biological / Disease Relevance
Spinal muscular atrophy (SMA), pre-mRNA splicing
In vitro activity
SMN2 protein expression assay (EC50)In vitro activity
SMN2 expression assay - patient fibroblast (EC50)Target Information
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron protein SMN. The SMN locus on chromosome 5q13 contains two inverted copies of SMN, called SMN1 and SMN2, which are 99% identical at the amino acid level. At the splicing level, SMN1 mainly produces one splice variant (90%) containing exons 1-8; this variant is identified as SMN protein, which is the fully functional protein. Protein from SMN2 expression excludes exon 7 90% of the time. Skipping of exon 7 produces non-functional SMN protein product. In the SMA disease state, various mutations in the SMN1 locus render that protein nonfunctional and induce the disease state. The 10% of SMN2 translation that yields SMN protein is not sufficient to overcome the deficiency produced by the loss of the SMN1 expression product. A therapy to either increase the amount of SMN2 product made, or to increase the inclusion of exon 7, has been proposed for the treatment of SMA.
ML103 is useful for modulating the expression of SMN2 protein in cell-based models of SMN protein expression. This probe has not been evaluated for use in vivo, though it has been shown to increase SMN2 protein production in fibroblasts derived from SMA patients. This suggests that the probe could alter the splicing of the SMN2 protein.
Properties
ML104
MLS000763654
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 263.29 g/mol | |||
| Molecular Formula | C16H13N3O | |||
| cLogP | 2.8 | |||
| PSA | 47.9 | |||
| Storage | ||||
| Solubility | ||||
| CAS Number | ||||
SMILES:
COC1=NC(C2=CC=CC=C2)=NN=C1C3=CC=CC=C3
InChI:
InChI=1S/C16H13N3O/c1-20-16-14(12-8-4-2-5-9-12)18-19-15(17-16)13-10-6-3-7-11-13/h2-11H,1H3
InChIKey:
YPJMIXQBDVYQRG-UHFFFAOYSA-N
Activity
Summary activity statement /
Previous probes have worked through non-specific mechanisms of activation (HDAC inhibition, RNA decapping), and effect an increase in protein abundance in both SMN2 and SMN1 reporter cell lines. ML104 (CID 6404603; SID 24819285) appears to operate through a unique mechanism of action, showing an increase in SMN2 protein production without having an effect on SMN1 protein production in the analogous cell line. Moreover, this probeexhibit a similar activity in the patient fibroblast SMN2 expression assay.
Figure 4. SMN protein abundance in patient fibroblasts after incubation with probe molecule. Sodium butyrate was used as a positive control; it has been observed to increase SMN protein roughly 10-fold. The probe molecule effected an approximately 2-fold increase in protein abundance at 1 micromolar compound concentration.
In vitro activity - Selectivity Assay
| SMN2 | ML104 |
|---|---|
|
SMN2 protein expression (EC50) |
2.5 uM |
|
SMN1 protein expression (EC50) |
> 50 uM |
Summary /
ML104 is observed to be 10-fold selective for SMN2 versus SMN1 expression in reporter-based assays.
References
- Quantitative High-Throughput Screen for Enhancers of SMN2 Splice Variant Expression: Summary
- Titus S, Marugan J, Southall N, et al. High throughput screening for SMA. 2009 May 18 [Updated 2010 Sep 2]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47357/