Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)
| Autor: | Natalie Dales, Monish Jain, Sanchez Carina Cristina, Ryan Kerrigan, Atwood K. Cheung, Cary Fridrich, Donovan N. Chin, Brian Hurley, Keith Hoffmaster, Lin Deng, Ronald Tomlinson, Marc Hild, Rajeev Sivasankaran, Jake Axford, Aleem Fazal, Gary O’Brien, Christopher Towler, Mailin Van Hoosear, Youngah Shin, Dione Kobayashi, Shen Yiping, Lei Shu, William F. Dietrich, Karen S. Chen, Lawrence G. Hamann, Karin Briner, Rebecca Servais, Cheng Song, Emma Cody, Robert Sun, Daniel Curtis, Moo Je Sung, Ying Hou |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
ERG1 Potassium Channel Spliceosome RNA Splicing Phenotypic screening Drug Evaluation Preclinical Administration Oral Quantitative Structure-Activity Relationship SMN1 Crystallography X-Ray Cell Line Muscular Atrophy Spinal Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Animals Humans Gene Motor Neurons Dose-Response Relationship Drug Chemistry Brain Spinal muscular atrophy Motor neuron medicine.disease SMA Survival of Motor Neuron 1 Protein nervous system diseases Mice Inbred C57BL Pyridazines Survival of Motor Neuron 2 Protein 030104 developmental biology medicine.anatomical_structure RNA splicing Molecular Medicine Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 61:11021-11036 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01291 |
| Popis: | Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA. |
| Databáze: | OpenAIRE |
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