Document Detail

A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene.
MedLine Citation:
PMID:  23774824     Owner:  NLM     Status:  MEDLINE    
Chemical-induced read through of premature stop codons might be exploited as a potential treatment strategy for genetic disorders caused by nonsense mutations. Despite the promise of this approach, only a few read-through compounds (RTCs) have been discovered to date. These include aminoglycosides (e.g., gentamicin and G418) and nonaminoglycosides (e.g., PTC124 and RTC13). The therapeutic benefits of these RTCs remain to be determined. In an effort to find new RTCs, we screened an additional ~36,000 small molecular weight compounds using a high-throughput screening (HTS) assay that we had previously developed and identified two novel RTCs, GJ071, and GJ072. The activity of these two compounds was confirmed in cells derived from ataxia telangiectasia (A-T) patients with three different types of nonsense mutation in the ATM gene. Both compounds showed activity comparable to stop codons (TGA, TAG, and TAA) PTC124 and RTC13. Early structure-activity relationship studies generated eight active analogs of GJ072. Most of those analogs were effective on all three stop codons. GJ071 and GJ072, and some of the GJ072 analogs, appeared to be well tolerated by A-T cells. We also identified another two active RTCs in the primary screen, RTC204 and RTC219, which share a key structural feature with GJ072 and its analogs.
Liutao Du; Michael E Jung; Robert Damoiseaux; Gladys Completo; Francesca Fike; Jin-Mo Ku; Shareef Nahas; Cijing Piao; Hailiang Hu; Richard A Gatti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-06-18
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-09-06     Completed Date:  2014-03-26     Revised Date:  2014-09-02    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1653-60     Citation Subset:  IM    
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MeSH Terms
Acetanilides / chemistry,  pharmacology*
Ataxia Telangiectasia / drug therapy*,  genetics
Ataxia Telangiectasia Mutated Proteins / genetics*,  metabolism
Benzodioxoles / chemistry,  pharmacology*
Cells, Cultured
Codon, Nonsense*
Codon, Terminator / drug effects*
DNA-Binding Proteins / genetics
High-Throughput Screening Assays
Molecular Targeted Therapy
Molecular Weight
Small Molecule Libraries
Structure-Activity Relationship
Thiourea / analogs & derivatives*,  chemistry,  pharmacology
Triazoles / chemistry,  pharmacology*
Grant Support
Reg. No./Substance:
0/Acetanilides; 0/Benzodioxoles; 0/Codon, Nonsense; 0/Codon, Terminator; 0/DNA-Binding Proteins; 0/GJ071 compound; 0/GJ072 compound; 0/Small Molecule Libraries; 0/Triazoles; EC protein, human; EC Telangiectasia Mutated Proteins; GYV9AM2QAG/Thiourea
Comment In:
Mol Ther. 2013 Sep;21(9):1650-2   [PMID:  24008619 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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