Hurley, Timothy, Kerrigan, John, Shu, Lei, Shen, Yiping, Sung, Moo, O'Brien, Gary, Hou, Ying, Axford, Jake, Deng, Lin, Hoffmaster, Keith, Shin, Youngah, Servais, Rebecca, Towler, Christopher, Hild, Marc, Briner, Karin, Dietrich, Bill, Sivasankaran, Rajeev, Dales, Natalie, Chin, Donovan, Sun, Robert, Cody, Emma, Fazal, Aleem, Tomlinson, Ronald, Song, Cheng, Jain, Monish, Van Hoosear, Mailin, Hamann, Lawrence, Curtis, Daniel, Kobayashi, Dione, Chen, Karen, 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