Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases.

Chemical modifications of G418 (geneticin): Synthesis of novel readthrough aminoglycosides results in an improved in vitro safety window but no improvements in vivo.

G418 is currently the most potent and active aminoglycoside to promote readthrough of eukaryotic nonsense mutations. However, owing to its toxicity G418 cannot be used in vivo to study readthrough activity A robust and scalable method for selective derivatization of G418 was developed to study the biological activity and toxicity of a series of analogs. Despite our synthetic efforts, an improvement in readthrough potency was not achieved.

The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential.

Nonsense mutations, resulting in a premature stop codon in the open reading frame of mRNAs are responsible for thousands of inherited diseases. Readthrough of premature stop codons by small molecule drugs has emerged as a promising therapeutic approach to treat disorders resulting from premature termination of translation. The aminoglycoside antibiotics are a class of molecule known to promote readthrough at premature termination codons.

The nucleoside analog clitocine is a potent and efficacious readthrough agent.

Nonsense mutations resulting in a premature stop codon in an open reading frame occur in critical tumor suppressor genes in a large number of the most common forms of cancers and are known to cause or contribute to the progression of disease. Low molecular weight compounds that induce readthrough of nonsense mutations offer a new means of treating patients with genetic disorders or cancers resulting from nonsense mutations. We have identified the nucleoside analog clitocine as a potent and efficacious suppressor of nonsense mutations.