Details

Autor(en) / Beteiligte

• Cheung, Atwood K
• Hurley, Brian
• Kerrigan, Ryan
• Shu, Lei
• Chin, Donovan N
• Shen, Yiping
• O’Brien, Gary
• Sung, Moo Je
• Hou, Ying
• Axford, Jake
• Cody, Emma
• Sun, Robert
• Fazal, Aleem
• Tomlinson, Ronald C
• Jain, Monish
• Deng, Lin
• Hoffmaster, Keith
• Song, Cheng
• Van Hoosear, Mailin
• Shin, Youngah
• Servais, Rebecca
• Towler, Christopher
• Hild, Marc
• Curtis, Daniel
• Dietrich, William F
• Hamann, Lawrence G
• Briner, Karin
• Chen, Karen S
• Kobayashi, Dione
• Sivasankaran, Rajeev
• Dales, Natalie A

Titel

Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron‑2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

Ist Teil von

• Journal of medicinal chemistry, 2018-12, Vol.61 (24), p.11021-11036

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.