Journal of Medicinal Chemistry p. 6070 - 6085 (2016)
Update date:2022-08-15
Topics:
Woll, Matthew G.
Qi, Hongyan
Turpoff, Anthony
Zhang, Nanjing
Zhang, Xiaoyan
Chen, Guangming
Li, Chunshi
Huang, Song
Yang, Tianle
Moon, Young-Choon
Lee, Chang-Sun
Choi, Soongyu
Almstead, Neil G.
Naryshkin, Nikolai A.
Dakka, Amal
Narasimhan, Jana
Gabbeta, Vijayalakshmi
Welch, Ellen
Zhao, Xin
Risher, Nicole
Sheedy, Josephine
Weetall, Marla
Karp, Gary M.
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.
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