Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy
| Autor: | Tianle Yang, Hasane Ratni, Emmanuel Pinard, Nanjing Zhang, Hongyan Qi, Nikolai Naryshkin, Priya Vazirani, Stephan Kirchner, Xiaoyan Zhang, Karen S. Chen, Amal Dakka, Lutz Mueller, Friedrich Metzger, Woll Matthew G, Sergey Paushkin, Xin Zhao, Marla Weetall, Gary Mitchell Karp, Kathleen D. McCarthy, Agnès Poirier, Wolfgang Muster, Pascale David-Pierson, Luke Green, Irene Gerlach, Anthony Turpoff, Dietrich Tuerck |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pyrimidinones SMN1 Biology medicine.disease_cause Muscular Atrophy Spinal Mice 03 medical and health sciences Exon 0302 clinical medicine Drug Discovery medicine Animals Humans RNA Messenger Genetics Messenger RNA Mutation Alternative splicing Exons Spinal muscular atrophy medicine.disease SMA nervous system diseases Survival of Motor Neuron 2 Protein Alternative Splicing 030104 developmental biology RNA splicing Cancer research Molecular Medicine 030217 neurology & neurosurgery |
| Zdroj: | Journal of Medicinal Chemistry. 59:6086-6100 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMNΔ7 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of full-length SMN2 mRNA. Upon oral administration of our small molecules, the levels of full-length SMN protein were restored in two mouse models of SMA. In-depth lead optimization in the pyridopyrimidinone series culminated in the selection of compound 3 (RG7800), the first small molecule SMN2 splicing modifier to enter human clinical trials. |
| Databáze: | OpenAIRE |
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