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

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.