ABSTRACT
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.
Subject(s)
Acetanilides/pharmacology , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia/drug therapy , Benzodioxoles/pharmacology , Codon, Nonsense , Codon, Terminator/drug effects , Thiourea/analogs & derivatives , Triazoles/pharmacology , Acetanilides/chemistry , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Benzodioxoles/chemistry , Cells, Cultured , DNA-Binding Proteins/genetics , High-Throughput Screening Assays , Humans , Molecular Targeted Therapy , Molecular Weight , Small Molecule Libraries , Structure-Activity Relationship , Thiourea/chemistry , Thiourea/pharmacology , Triazoles/chemistryABSTRACT
OBJECTIVE: The American College of Rheumatology (ACR) and the Association of Rheumatology Health Professionals (ARHP) Annual Scientific Meeting is an important forum for early dissemination of novel ideas. However, unlike published studies in peer-reviewed journals, reviewers select abstracts based solely on a general summary of the research. Analyses of the scientific impact and the publication record of the ACR/ARHP Annual Meeting have not been previously described. This study characterizes publication trends and outcomes associated with abstracts presented at the ACR/ARHP Annual Scientific Meeting. METHODS: We identified all abstracts accepted for oral or poster presentation at the 2006 ACR/ARHP Annual Scientific Meeting. Using a defined search algorithm, we conducted a manual PubMed search for each accepted abstract, which was repeated by a custom computerized search, and analyzed the resulting journal title, impact factor, and time to publication. RESULTS: A total of 2,149 abstracts were analyzed. The overall publication ratio was 59.1%. The mean ± SD time from abstract presentation to publication was 18.2 ± 15.2 months with a mean ± SD impact factor of 5.61 ± 4.20. Overall, studies presented in oral format were significantly more likely to be published than poster presentations (P < 0.0001). The average time to publication was significantly shorter for basic science studies than clinical research studies (P < 0.0001). The average journal impact factor of published studies presented in oral format was significantly higher than those presented as posters (P < 0.0001). CONCLUSION: These results reflect high research productivity with a publication ratio of approximately 60% for abstracts presented at the 2006 Annual Scientific Meeting.
