1. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.
- Author
-
Rietz A, Li H, Quist KM, Cherry JJ, Lorson CL, Burnett BG, Kern NL, Calder AN, Fritsche M, Lusic H, Boaler PJ, Choi S, Xing X, Glicksman MA, Cuny GD, Androphy EJ, and Hodgetts KJ
- Subjects
- Anilides pharmacokinetics, Anilides therapeutic use, Area Under Curve, Benzamides pharmacokinetics, Benzamides therapeutic use, Cell Line, Drug Discovery, Half-Life, Humans, Isoxazoles pharmacokinetics, Isoxazoles therapeutic use, Protein Stability, Quinolones pharmacokinetics, Quinolones therapeutic use, Structure-Activity Relationship, Thiazoles pharmacokinetics, Thiazoles therapeutic use, Anilides pharmacology, Benzamides pharmacology, Isoxazoles pharmacology, Molecular Probes, Muscular Atrophy, Spinal therapy, Protein Processing, Post-Translational, Quinolones pharmacology, Survival of Motor Neuron 1 Protein metabolism, Thiazoles pharmacology
- 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.
- Published
- 2017
- Full Text
- View/download PDF