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.




Copyright 2017 Journal of Medicinal Chemistry. This is a post-print of a published paper that is available at: Recommended citation: Rietz, Anne, Hongxia Li, Kevin M. Quist, Jonathan J. Cherry, Christian L. Lorson, Barrington G. Burnett, Nicholas L. Kern et al. "Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy." Journal of medicinal chemistry 60, no. 11 (2017): 4594-4610. doi: 10.1021/acs.jmedchem.6b01885. This item has been deposited in accordance with publisher copyright and licensing terms and wit hthe author's permission.