| Literature DB >> 30407821 |
Atwood K Cheung1, Brian Hurley1, Ryan Kerrigan1, Lei Shu1, Donovan N Chin1, Yiping Shen1, Gary O'Brien1, Moo Je Sung1, Ying Hou1, Jake Axford1, Emma Cody1, Robert Sun1, Aleem Fazal1, Cary Fridrich1, Carina C Sanchez1, Ronald C Tomlinson1, Monish Jain1, Lin Deng1, Keith Hoffmaster1, Cheng Song1, Mailin Van Hoosear1, Youngah Shin1, Rebecca Servais1, Christopher Towler2, Marc Hild1, Daniel Curtis1, William F Dietrich1, Lawrence G Hamann1, Karin Briner1, Karen S Chen3, Dione Kobayashi3, Rajeev Sivasankaran1, Natalie A Dales1.
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 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.Entities:
Mesh：
Substances：
Year: 2018 PMID： 30407821 DOI： 10.1021/acs.jmedchem.8b01291
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446