ArticleJournal of medicinal chemistry2017
Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.
Article in Journal of medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed, 16 citations in OpenAlex.
- Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy.Scientific reports · 2023Article
- Synthesis and structure-activity relationship study of new biaryl amide derivatives and their inhibitory effects against hepatitis C virus.European journal of medicinal chemistry · 2022Article
- Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy.Life science alliance · 2021Article
- Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy.Scientific reports · 2019Article
- Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers.Bioorganic & medicinal chemistry letters · 2017Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.