Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy

Rietz Anne; Li Hongxia; Quist Kevin M.; Cherry Jonathan J.; Lorson Christian L.; Burnett Barrington G.; Kern Nicholas L.; Calder Alyssa N.; Fritsche Melanie; Lusic Hrvoje; Boaler Patrick J.; Choi Sungwoon; Xing Xuechao; Glicksman Marcie A.; Cuny Gregory D.; Androphy Elliot J.; Hodgetts Kevin J.

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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

机译：发现一种小分子探针，可翻译后稳定存活运动神经元蛋白，用于治疗脊髓肌萎缩

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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.

机译：脊柱肌肉萎缩（SMA）是婴儿死亡的主要遗传原因。我们以前开发了一种高通量测定，采用SMN2-荧光素酶报告称，允许鉴定转录的化合物，增强外显子识别或稳定SMN蛋白。我们描述了适用于体内测试的模拟的优化和表征。最初，我们鉴定了由于短等离子体稳定性，在小鼠PK实验中具有良好的体外特性但低血浆和脑暴露的模拟4m; 通过逆转酰胺键并改变杂环来克服这一点。噻唑27显示出优异的体外性质和有前途的小鼠PK型材，使其适用于体内测试。本系列翻译后稳定了SMN蛋白，与全球蛋白酶体或自噬抑制无关，揭示了一种新的治疗机制，应该补充其他方式治疗SMA。

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《Journal of Medicinal Chemistry》 |2017年第11期|共17页
作者
Rietz Anne; Li Hongxia; Quist Kevin M.; Cherry Jonathan J.; Lorson Christian L.; Burnett Barrington G.; Kern Nicholas L.; Calder Alyssa N.; Fritsche Melanie; Lusic Hrvoje; Boaler Patrick J.; Choi Sungwoon; Xing Xuechao; Glicksman Marcie A.; Cuny Gregory D.; Androphy Elliot J.; Hodgetts Kevin J.;
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Indiana Univ Sch Med Dept Dermatol Indianapolis IN 46202 USA;

Indiana Univ Sch Med Dept Dermatol Indianapolis IN 46202 USA;

Indiana Univ Sch Med Dept Dermatol Indianapolis IN 46202 USA;

Indiana Univ Sch Med Dept Dermatol Indianapolis IN 46202 USA;

Univ Missouri Dept Vet Pathobiol Bond Life Sci Ctr Columbia MO 65201 USA;

Uniformed Serv Univ Hlth Sci F Edward Hebert Sch Med Dept Anat Physiol &

Genet Bethesda MD 20814 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

Indiana Univ Sch Med Dept Dermatol Indianapolis IN 46202 USA;

Brigham &

Womens Hosp Lab Drug Discovery Neurodegenerat 65 Landsdowne St Cambridge MA 02139 USA;

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1. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy [J] . Rietz Anne, Li Hongxia, Quist Kevin M., Journal of Medicinal Chemistry . 2017,第11期

机译：发现一种小分子探针，可翻译后稳定存活运动神经元蛋白，用于治疗脊髓肌萎缩
2. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy [J] . Woll Matthew G., Qi Hongyan, Turpoff Anthony, Journal of Medicinal Chemistry . 2016,第13期

机译：发现和优化的生存运动神经元2小分子剪接修饰剂治疗脊髓性肌萎缩症。
3. Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy [J] . Ratni Hasane, Karp Gary M., Weetall Marla, Journal of Medicinal Chemistry . 2016,第13期

机译：小分子替代生存运动神经元2拼接的具体校正：一种潜在的新型药物治疗脊髓性肌萎缩的发现。
4. Early decrease of survival signal protein and DNA repair enzyme in spinal motor neuron of presymptomatic transgenic mice with a mutant SOD1 gene [C] . M. Shiote, H. Ilieva, I. Nagano, International Symposium on Molecular Mechanism and Epochal Therapeutics for Ischemic Stroke and Dementia . 2003

机译：用突变SOD1基因早期降低生存信号蛋白和脊柱运动神经元中的脊髓运动神经元的DNA修复酶
5. Investigating the pre-mRNA splicing of the Survival Motor Neuron genes to model the Spinal Muscular Atrophy disease phenotype. [D] . Gladman, Jordan Tanin. 2010

机译：研究生存运动神经元基因的mRNA前剪接，以建模脊髓性肌萎缩症疾病表型。
6. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy [O] . Anne Rietz, Hongxia Li, Kevin M. Quist, -1

机译：小分子探针的翻译后稳定生存运动神经元蛋白治疗脊髓性肌萎缩症的发现。
7. Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron [O] . Ke-Jun Han, Daniel G. Foster, Nan-Yan Zhang, 2012

机译：泛素特异性蛋白酶9x脱硫蛋白酶并稳定脊髓肌萎缩蛋白 - 存活运动神经元
8. Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients with Spinal Muscular Atrophy (SMA). [R] . De Vivo, D. C. 2012

机译：哥伦比亚sma项目：运动对脊髓性肌萎缩症（sma）患者运动功能和力量影响的随机对照试验。

Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy

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