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

Anne Rietz, Hongxia Li, Kevin M. Quist, Jonathan J. Cherry, Christian L. Lorson, Barrington G. Burnett, Nicholas L. Kern, Alyssa N. Calder, Melanie Fritsche, Hrvoje Lusic, Patrick J. Boaler, Sungwoon Choi, Xuechao Xing, Marcie A. Glicksman, Gregory D. Cuny, Elliot J. Androphy, Kevin J. Hodgetts

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4594-4610
Number of pages17
JournalJournal of Medicinal Chemistry
Volume60
Issue number11
DOIs
StatePublished - Jun 8 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Rietz, A., Li, H., Quist, K. M., Cherry, J. J., Lorson, C. L., Burnett, B. G., Kern, N. L., Calder, A. N., Fritsche, M., Lusic, H., Boaler, P. J., Choi, S., Xing, X., Glicksman, M. A., Cuny, G. D., Androphy, E. J., & Hodgetts, K. J. (2017). 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(11), 4594-4610. https://doi.org/10.1021/acs.jmedchem.6b01885