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

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posted on 08.11.2018, 00:00 authored by Atwood K. Cheung, Brian Hurley, Ryan Kerrigan, Lei Shu, Donovan N. Chin, Yiping Shen, Gary O’Brien, Moo Je Sung, Ying Hou, Jake Axford, Emma Cody, Robert Sun, Aleem Fazal, Cary Fridrich, Carina C. Sanchez, Ronald C. Tomlinson, Monish Jain, Lin Deng, Keith Hoffmaster, Cheng Song, Mailin Van Hoosear, Youngah Shin, Rebecca Servais, Christopher Towler, Marc Hild, Daniel Curtis, William F. Dietrich, Lawrence G. Hamann, Karin Briner, Karen S. Chen, Dione Kobayashi, Rajeev Sivasankaran, Natalie A. Dales
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.