Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy

作者：Matthew G. Woll, Hongyan Qi, Anthony Turpoff, Nanjing Zhang, Xiaoyan Zhang, Guangming Chen, Chunshi Li, Song Huang, Tianle Yang, Young‐Choon Moon, Chang-Sun Lee, Soongyu Choi, Neil G. Almstead, Nikolai A. Naryshkin, Amal Dakka, Jana Narasimhan, Vijayalakshmi Gabbeta, Ellen Welch, Xin Zhao, Nicole Risher, Josephine Sheedy, Marla Weetall, Gary M. Karp · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b00460 · 被引用次数：61 · 研究领域：Neurogenetic and Muscular Disorders Research、RNA Research and Splicing、RNA modifications and cancer

The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.