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

• Published in: Journal of medicinal chemistry Vol. 61; no. 24; pp. 11021 - 11036
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.12.2018; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; MODIFIERS; IDENTIFICATION; SINGLE NUCLEOTIDE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b01291

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.