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

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

  • J Med Chem. 2017 Jun 8;60(11):4594-4610. doi: 10.1021/acs.jmedchem.6b01885.
Anne Rietz 1,  Hongxia Li 1,  Kevin M Quist 1,  Jonathan J Cherry 1,  Christian L Lorson 2,  Barrington G Burnett 3,  Nicholas L Kern 4,  Alyssa N Calder 4,  Melanie Fritsche 4,  Hrvoje Lusic 4,  Patrick J Boaler 4,  Sungwoon Choi 4,  Xuechao Xing 4,  Marcie A Glicksman 4,  Gregory D Cuny 4,  Elliot J Androphy 1,  Kevin J Hodgetts 4
Affiliations

Affiliations

  • 1 Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
  • 2 Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65201, United States.
  • 3 Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda, Maryland 20814, United States.
  • 4 Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
PMID: 28481536 DOI: 10.1021/acs.jmedchem.6b01885
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.

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