Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy

Matthew E.R. Butchbach*, Jasbir Singh, Margrét Thorsteinsdóttir, Luciano Saieva, Elzbieta Slominski, John Thurmond, Thorkell Andrésson, Jun Zhang, Jonathan D. Edwards, Louise R. Simard, Livio Pellizzoni, Jill Jarecki, Arthur H.M. Burghes, Mark E. Gurney

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)


Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN lacking exon 7 (SMNΔ7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNΔ7 SMA mice by ~21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMNΔ7 SMA mice.

Original languageEnglish
Article numberddp510
Pages (from-to)454-467
Number of pages14
JournalHuman Molecular Genetics
Issue number3
Publication statusPublished - 6 Nov 2009

Bibliographical note

Funding Information:
The development of the quinazoline compound and the testing in the SMA mice were financially supported in its entirety by Families of SMA (to M.E.R.B., A.H.M.B. and M.E.G.). The establishment and maintenance of the mice used in this study were funded in part by the National Institutes of Health (NS38650 to A.H.M.B.) and the Miracles for Madison Fund (to A.H.M.B.). The snRNP assembly assays were funded by the SMA Foundation and the Motor Neuron Center of Columbia University (to L.P.).


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