Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy.
J Med Chem
; 59(13): 6086-100, 2016 07 14.
Article
em En
| MEDLINE
| ID: mdl-27299419
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinonas
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RNA Mensageiro
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Atrofia Muscular Espinal
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Processamento Alternativo
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Proteína 2 de Sobrevivência do Neurônio Motor
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article