ArticleHuman molecular genetics2013
The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 2 of them syntheses that pooled it.
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Who cites it
58 citing papers in PubMed, 2 syntheses or guidelines pooled it, 88 citations in OpenAlex.
- Drug treatment for spinal muscular atrophy types II and III.The Cochrane database of systematic reviews · 2020Pooled it
- Drug treatment for spinal muscular atrophy type I.The Cochrane database of systematic reviews · 2019Pooled it
- Article
- The effect of coadministration of D156844 and AR42 (REC-2282) on the survival and motor phenotype of mice with spinal muscular atrophy.Scientific reports · 2025Article
- DCPS is a synthetic lethal therapeutic target in acute myeloid leukemia expressing low levels of FHIT.Leukemia · 2025Article
- Aberrant pre-mRNA processing in cancer.The Journal of experimental medicine · 2024Review
- Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma.Journal of translational medicine · 2024Article
- Evaluation of the orally bioavailable 4-phenylbutyrate-tethered trichostatin A analogue AR42 in models of spinal muscular atrophy.Scientific reports · 2023Article
- Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki-Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors.The Journal of organic chemistry · 2023Article
- Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.ACS chemical biology · 2022Article
- Evaluation of carboxyfluorescein-labeled 7-methylguanine nucleotides as probes for studying cap-binding proteins by fluorescence anisotropy.Scientific reports · 2021Article
- Targeting the 5' untranslated region ofMolecular therapy. Nucleic acids · 2021Article
- Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the SmnExperimental neurology · 2021Article
- In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy.Brain sciences · 2021Review
- Small molecule targeting of RNA structures in neurological disorders.Annals of the New York Academy of Sciences · 2020Review
- Hallmarks of Splicing Defects in Cancer: Clinical Applications in the Era of Personalized Medicine.Cancers · 2020Review
- Effect of the His-Tag Location on Decapping Scavenger Enzymes and Their Hydrolytic Activity toward Cap Analogs.ACS omega · 2020Article
- New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?International journal of molecular sciences · 2020Review
- Synthesis of Trifluoromethylated Purine Ribonucleotides and Their Evaluation asThe Journal of organic chemistry · 2020Article
- Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment.Frontiers in pharmacology · 2020Review
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 1 country.
Funding
Abstract
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/- SMA mice), and positively impacts neuromuscular pathologies. In 2B/- SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/- SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects.
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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.