Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy
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DOI：
10.1093/hmg/ddp510
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发表时间：
2010-02-01
影响因子：
3.5
通讯作者：
Gurney, Mark E.
中科院分区：
文献类型：
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作者：
Butchbach, Matthew E. R.;Singh, Jasbir;Gurney, Mark E.
近端脊髓性肌萎缩症（SMA）是婴儿死亡的最常见遗传原因之一，是由于脊髓中运动神经元的选择性丧失。SMA是运动神经元存活蛋白（SMN）水平低的结果。在人类中，SMN基因是重复的; SMA是由SMN 1的丢失引起的，但SMN 2保持完整。SMA严重程度与SMN 2拷贝数相关。因此，增加SMN 2表达的化合物可能是SMA的潜在治疗剂。超高通量筛选最近确定取代喹唑啉作为有效的SMN 2诱导剂。测试了一系列C5-喹唑啉衍生物在体内增加SMN表达的能力。三种化合物（D152344，D153249和D156844）的新生小鼠口服给药导致中枢神经系统中Smn启动子活性的剂量依赖性增加。然后，我们检查了这些化合物对SMN缺失外显子7（SMN delta 7）SMA小鼠疾病进展的影响。在运动神经元丧失前经口给予D156844可显著延长SMN delta 7 SMA小鼠的平均寿命，增幅约为21-30%。总之，C5-喹唑啉衍生物D156844增加了新生小鼠神经组织中的SMN表达，延迟了PND 11时的运动神经元损失，并改善了SMN δ 7 SMA小鼠的运动表型。
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 delta 7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMN delta 7 SMA mice by similar to 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 SMN delta 7 SMA mice.