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Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-08 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01885 Anne Rietz 1 , Hongxia Li 1 , Kevin M. Quist 1 , Jonathan J. Cherry 1 , Christian L. Lorson 2 , Barrington G. Burnett 3 , Nicholas L. Kern 4 , Alyssa N. Calder 4 , Melanie Fritsche 4 , Hrvoje Lusic 4 , Patrick J. Boaler 4 , Sungwoon Choi 4 , Xuechao Xing 4 , Marcie A. Glicksman 4 , Gregory D. Cuny 4 , Elliot J. Androphy 1 , Kevin J. Hodgetts 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-08 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01885 Anne Rietz 1 , Hongxia Li 1 , Kevin M. Quist 1 , Jonathan J. Cherry 1 , Christian L. Lorson 2 , Barrington G. Burnett 3 , Nicholas L. Kern 4 , Alyssa N. Calder 4 , Melanie Fritsche 4 , Hrvoje Lusic 4 , Patrick J. Boaler 4 , Sungwoon Choi 4 , Xuechao Xing 4 , Marcie A. Glicksman 4 , Gregory D. Cuny 4 , Elliot J. Androphy 1 , Kevin J. Hodgetts 4
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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
中文翻译：
小分子探针的发现，其翻译后稳定了存活运动神经元蛋白，用于治疗脊髓性肌萎缩症
脊髓性肌萎缩症（SMA）是婴儿死亡的主要原因。我们之前开发了一种高通量测定方法，该方法采用SMN2-荧光素酶报道分子，可鉴定具有转录作用，增强外显子识别或稳定SMN蛋白的化合物。我们描述了适用于体内测试的类似物的优化和表征。最初，我们在小鼠PK实验中鉴定出具有良好体外特性但血浆和脑暴露量较低的类似物4m，这是由于血浆稳定性差；通过逆转酰胺键和改变杂环可以克服这一问题。噻唑27显示出优异的体外性能和有希望的小鼠PK谱，使其适用于体内测试。该系列翻译后稳定了与整体蛋白酶体或自噬抑制作用无关的SMN蛋白，揭示了一种新颖的治疗机制，该机制应与其他治疗SMA的方式相辅相成。
更新日期：2017-05-20
中文翻译：
小分子探针的发现，其翻译后稳定了存活运动神经元蛋白，用于治疗脊髓性肌萎缩症
脊髓性肌萎缩症（SMA）是婴儿死亡的主要原因。我们之前开发了一种高通量测定方法，该方法采用SMN2-荧光素酶报道分子，可鉴定具有转录作用，增强外显子识别或稳定SMN蛋白的化合物。我们描述了适用于体内测试的类似物的优化和表征。最初，我们在小鼠PK实验中鉴定出具有良好体外特性但血浆和脑暴露量较低的类似物4m，这是由于血浆稳定性差；通过逆转酰胺键和改变杂环可以克服这一问题。噻唑27显示出优异的体外性能和有希望的小鼠PK谱，使其适用于体内测试。该系列翻译后稳定了与整体蛋白酶体或自噬抑制作用无关的SMN蛋白，揭示了一种新颖的治疗机制，该机制应与其他治疗SMA的方式相辅相成。
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