Phenotypic Drug Discovery
Chapter 8: Identification of a Novel Class of Small Molecules for Spinal Muscular Atrophy Through High-throughput Phenotypic Screening
Published:09 Dec 2020
Special Collection: 2020 ebook collectionSeries: Drug Discovery
S. E. Swalley and A. K. Cheung, in Phenotypic Drug Discovery, ed. B. Isherwood and A. Augustin, The Royal Society of Chemistry, 2020, ch. 8, pp. 140-159.
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Spinal muscular atrophy (SMA) is a devastating neuromuscular disease that historically was the leading genetic cause of infant mortality, with no US Food and Drug Administration-approved therapies until 2016. SMA is a monogenic disease caused by the loss or mutation of the survival of motor neuron 1 (SMN1) gene. There is a nearly identical paralog gene, SMN2, that predominantly produces truncated and unstable SMN protein due to a silent mutation that results in exon 7 skipping in the majority of transcripts. However, SMN2 does produce a small amount of full-length protein, with an inverse correlation between disease severity and the number of SMN2 copies, indicating that increasing levels of SMN protein could help patients by preventing motor neuron degeneration. This chapter guides readers through the phenotypic discovery of low molecular weight splicing modulators that increase levels of SMN protein, highlighting the screening assay, compound triage, translation to relevant disease models, and mechanism of action studies. We will discuss key factors, of which some are SMA-specific and some are more generally applicable, that led to the successful development of these small molecules through a target-agnostic phenotypic approach.