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2-Aminothiazole-4-carboxamides Enhance Readthrough of Premature Termination Codons by Aminoglycosides.

Abstract：

:Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and toxic at therapeutic doses. Library screening in assays that measure readthrough at a PTC in the TP53 gene in human HDQ-P1 cells identified six novel 2-aminothiazole-4-carboxamide derivatives that potentiate the PTC readthrough (PTCR) efficiency of G418 when used in combination. The two most potent compounds incorporated a 4-indazole motif on the 2-aminothiazole nitrogen and a hydrophobic aryl substituent on the carboxamide nitrogen. These compounds are valuable tools to further investigate the therapeutic potential of aminoglycoside-induced PTCR.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Rabea SM,Baradaran-Heravi A,Balgi AD,Krause A,Hosseini Farahabadi S,Roberge M,Grierson DS

doi

10.1021/acsmedchemlett.8b00610

subject

Has Abstract

pub_date

2019-04-09 00:00:00

pages

726-731

issue

5

issn

1948-5875

journal_volume

10

pub_type

杂志文章

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