62039-88-7Relevant academic research and scientific papers
COMPOSITIONS FOR PROMOTING READTHROUGH OF PREMATURE TERMINATION CODONS, AND METHODS OF USING THE SAME
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Page/Page column 214; 216; 217, (2017/04/11)
Disclosed are compounds of general formula (I) that promote readthrough of a premature termination codon (PTC) of an RNA molecule in a translation system, and their use, alone or in combination with other compounds, such as aminoglycoside, to treat diseases or disorders ameliorated by modulation of a premature termination codon (PTC) of an RNA molecule in a translation system. The disorder or disease may be Dystrophic epidermolysis bullosa, Batten disease, Duchenne muscular dystrophy, cancer, and spinal muscular atrophy. Ar-L-B (I)
Novel small molecules potentiate premature termination codon readthrough by aminoglycosides
Baradaran-Heravi, Alireza,Balgi, Aruna D.,Zimmerman, Carla,Choi, Kunho,Shidmoossavee, Fahimeh S.,Tan, Jason S.,Bergeaud, Célia,Krause, Alexandra,Flibotte, Stéphane,Shimizu, Yoko,Anderson, Hilary J.,Mouly, Vincent,Jan, Eric,Pfeifer, Tom,Jaquith, James B.,Roberge, Michel
, p. 6583 - 6598 (2016/09/09)
Nonsense mutations introduce premature termination codons and underlie 11% of genetic disease cases. High concentrations of aminoglycosides can restore gene function by eliciting premature termination codon readthrough but with low efficiency. Using a high-throughput screen, we identified compounds that potentiate readthrough by aminoglycosides at multiple nonsense alleles in yeast. Chemical optimization generated phthalimide derivative CDX5-1 with activity in human cells. Alone, CDX5-1 did not induce readthrough or increase TP53 mRNA levels in HDQ-P1 cancer cells with a homozygous TP53 nonsense mutation. However, in combination with aminoglycoside G418, it enhanced readthrough up to 180-fold over G418 alone. The combination also increased readthrough at all three nonsense codons in cancer cells with other TP53 nonsense mutations, as well as in cells from rare genetic disease patients with nonsense mutations in the CLN2, SMARCAL1 and DMD genes. These findings open up the possibility of treating patients across a spectrum of genetic diseases caused by nonsense mutations.
