title: Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.
abstract: 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 (SMNDelta7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 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 SMNDelta7 SMA mice.
authors.affiliation: Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. butchbach.1@osu.edu
authors.forename: Matthew E R
authors.initials: ME
authors.lastname: Butchbach
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Margrét
authors.initials: M
authors.lastname: Thorsteinsdóttir
authors.forename: Luciano
authors.initials: L
authors.lastname: Saieva
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Slominski
authors.forename: John
authors.initials: J
authors.lastname: Thurmond
authors.forename: Thorkell
authors.initials: T
authors.lastname: Andrésson
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Edwards
authors.forename: Louise R
authors.initials: LR
authors.lastname: Simard
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.forename: Jill
authors.initials: J
authors.lastname: Jarecki
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D011799:Quinazolines; D055540:Survival of Motor Neuron 2 Protein; C013474:2,4-diaminoquinazoline