Journal of Medicinal Chemistry p. 11021 - 11036 (2018)
Update date:2022-08-28
Topics:
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
Fridrich, Cary
Sanchez, Carina C.
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.
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.
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