Human Molecular Genetics Advance Access first published online on November 6, 2009
This version [Corrected Proof] published online on November 25, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp510
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
1 Department of Molecular and Cellular Biochemistry, 2 Department of Neurology, College of Medicine, and 3 Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, OH, USA, 4 deCODE chemistry, Inc., Woodridge, IL, USA, 5 deCODE genetics, Inc., Reykjavik, Iceland, 6 Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA, 7 Department of Biochemistry and Medical Genetics, University of Manitoba, Faculty of Medicine, Winnipeg, MB, Canada and 8 Families of SMA, Libertyville, IL, USA
* To whom correspondence should be addressed at: Department of Molecular and Cellular Biochemistry, 363 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: +1 6146884710 (M.E.R.B.)/+1 6146884759 (A.H.M.B.); Fax: +1 6142924118; Email: butchbach.1{at}osu.edu (M.E.R.B.)/burghes.1{at}osu.edu (A.H.M.B.)
Received September 2, 2009; Revised October 22, 2009; Accepted November 5, 2009
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 (SMN
7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMN7 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 SMN7 SMA mice.