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

Hurley, Timothy and Kerrigan, John and Shu, Lei and Shen, Yiping and Sung, Moo and O'Brien, Gary and Hou, Ying and Axford, Jake and Deng, Lin and Hoffmaster, Keith and Shin, Youngah and Servais, Rebecca and Towler, Christopher and Hild, Marc and Briner, Karin and Dietrich, Bill and Sivasankaran, Rajeev and Dales, Natalie and Chin, Donovan and Sun, Robert and Cody, Emma and Fazal, Aleem and Tomlinson, Ronald and Song, Cheng and Jain, Monish and Van Hoosear, Mailin and Hamann, Lawrence and Curtis, Daniel and Kobayashi, Dione and Chen, Karen and Fridrich, Cary and Sanchez, Carina (2018) Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). Journal of medicinal chemistry, 61 (24). pp. 11021-11036. ISSN 0022-2623

Abstract

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 multi-parameter 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.

Item Type: Article
Keywords: branaplam, LMI070, Spinal Muscular Atrophy, SMN2
Date Deposited: 28 May 2019 00:45
Last Modified: 28 May 2019 00:45
URI: https://oak.novartis.com/id/eprint/36963

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