Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy

Spinal muscular atrophy
(SMA) is the leading genetic cause of infant
death. We previously developed a high-throughput assay that employs
an SMN2-luciferase reporter allowing identification of compounds that
act transcriptionally, enhance exon recognition, or stabilize the
SMN protein. We describe optimization and characterization of an analog
suitable for in vivo testing. Initially,
we identified analog 4m that had good in vitro properties
but low plasma and brain exposure in a mouse PK experiment due to
short plasma stability; this was overcome by reversing the amide bond
and changing the heterocycle. Thiazole 27 showed excellent
in vitro properties and a promising mouse PK profile, making it suitable
for in vivo testing. This series post-translationally stabilizes the
SMN protein, unrelated to global proteasome or autophagy inhibition,
revealing a novel therapeutic mechanism that should complement other
modalities for treatment of SMA.