Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
Identifieur interne : 001B33 ( Main/Exploration ); précédent : 001B32; suivant : 001B34Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
Auteurs : Matthew E. R. Butchbach [États-Unis] ; Jasbir Singh ; Margrt Orsteinsdttir ; Luciano Saieva ; Elzbieta Slominski [Canada] ; John Thurmond ; Thorkell Andrsson ; Jun Zhang ; Jonathan D. Edwards ; Louise R. Simard [Canada] ; Livio Pellizzoni ; Jill Jarecki [États-Unis] ; Arthur H. M. Burghes [États-Unis] ; Mark E. GurneySource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-02-01.
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 (SMN7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMN7 SMA mice by 2130 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.
Url:
DOI: 10.1093/hmg/ddp510
Affiliations:
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Butchbach</name><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author><author><name sortKey="Singh, Jasbir" sort="Singh, Jasbir" uniqKey="Singh J" first="Jasbir" last="Singh">Jasbir Singh</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Orsteinsdttir, Margrt" sort="Orsteinsdttir, Margrt" uniqKey="Orsteinsdttir M" first="Margrt" last="Orsteinsdttir">Margrt Orsteinsdttir</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Saieva, Luciano" sort="Saieva, Luciano" uniqKey="Saieva L" first="Luciano" last="Saieva">Luciano Saieva</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Slominski, Elzbieta" sort="Slominski, Elzbieta" uniqKey="Slominski E" first="Elzbieta" last="Slominski">Elzbieta Slominski</name><affiliation wicri:level="4"><country>Canada</country><wicri:regionArea>Department of Biochemistry and Medical Genetics, University of Manitoba, Faculty of Medicine, Winnipeg, MB</wicri:regionArea><orgName type="university">Université du Manitoba</orgName><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author><author><name sortKey="Thurmond, John" sort="Thurmond, John" uniqKey="Thurmond J" first="John" last="Thurmond">John Thurmond</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Andrsson, Thorkell" sort="Andrsson, Thorkell" uniqKey="Andrsson T" first="Thorkell" last="Andrsson">Thorkell Andrsson</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Zhang, Jun" sort="Zhang, Jun" uniqKey="Zhang J" first="Jun" last="Zhang">Jun Zhang</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Edwards, Jonathan D" sort="Edwards, Jonathan D" uniqKey="Edwards J" first="Jonathan D." last="Edwards">Jonathan D. 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M." last="Burghes">Arthur H. M. Burghes</name><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author><author><name sortKey="Gurney, Mark E" sort="Gurney, Mark E" uniqKey="Gurney M" first="Mark E." last="Gurney">Mark E. Gurney</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-02-01">2010-02-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="454">454</biblScope><biblScope unit="page" to="467">467</biblScope></imprint><idno type="ISSN">0964-6906</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="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 (SMN7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMN7 SMA mice by 2130 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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Illinois</li><li>Manitoba</li></region><settlement><li>Winnipeg</li></settlement><orgName><li>Université du Manitoba</li></orgName></list><tree><noCountry><name sortKey="Andrsson, Thorkell" sort="Andrsson, Thorkell" uniqKey="Andrsson T" first="Thorkell" last="Andrsson">Thorkell Andrsson</name><name sortKey="Edwards, Jonathan D" sort="Edwards, Jonathan D" uniqKey="Edwards J" first="Jonathan D." last="Edwards">Jonathan D. Edwards</name><name sortKey="Gurney, Mark E" sort="Gurney, Mark E" uniqKey="Gurney M" first="Mark E." last="Gurney">Mark E. Gurney</name><name sortKey="Orsteinsdttir, Margrt" sort="Orsteinsdttir, Margrt" uniqKey="Orsteinsdttir M" first="Margrt" last="Orsteinsdttir">Margrt Orsteinsdttir</name><name sortKey="Pellizzoni, Livio" sort="Pellizzoni, Livio" uniqKey="Pellizzoni L" first="Livio" last="Pellizzoni">Livio Pellizzoni</name><name sortKey="Saieva, Luciano" sort="Saieva, Luciano" uniqKey="Saieva L" first="Luciano" last="Saieva">Luciano Saieva</name><name sortKey="Singh, Jasbir" sort="Singh, Jasbir" uniqKey="Singh J" first="Jasbir" last="Singh">Jasbir Singh</name><name sortKey="Thurmond, John" sort="Thurmond, John" uniqKey="Thurmond J" first="John" last="Thurmond">John Thurmond</name><name sortKey="Zhang, Jun" sort="Zhang, Jun" uniqKey="Zhang J" first="Jun" last="Zhang">Jun Zhang</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Butchbach, Matthew E R" sort="Butchbach, Matthew E R" uniqKey="Butchbach M" first="Matthew E. R." last="Butchbach">Matthew E. R. Butchbach</name></noRegion><name sortKey="Burghes, Arthur H M" sort="Burghes, Arthur H M" uniqKey="Burghes A" first="Arthur H. M." last="Burghes">Arthur H. M. Burghes</name><name sortKey="Jarecki, Jill" sort="Jarecki, Jill" uniqKey="Jarecki J" first="Jill" last="Jarecki">Jill Jarecki</name></country><country name="Canada"><region name="Manitoba"><name sortKey="Slominski, Elzbieta" sort="Slominski, Elzbieta" uniqKey="Slominski E" first="Elzbieta" last="Slominski">Elzbieta Slominski</name></region><name sortKey="Simard, Louise R" sort="Simard, Louise R" uniqKey="Simard L" first="Louise R." last="Simard">Louise R. Simard</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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