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. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.

使用小分子诱导提前终止密码子的通读是治疗由无义突变引起的遗传疾病和癌症的有前途的治疗方法，广泛使用 ataluren 治疗无义突变杜氏肌营养不良症就证明了这一点。在这里，我们描述了一系列新型胍基喹唑啉和嘧啶支架，它们在 HDQ-P1 乳腺癌细胞和mdx中诱导通读肌管。碱性叔胺与脂肪族疏水取代基与这些支架的末端胍氮的连接导致效力显着增加。通过在嘧啶环两侧添加疏水性取代基，在低至 120 nM 的浓度下诱导通读，并证明这些化合物与 ataluren 组合或作为独立治疗剂使用的潜力，进一步提高了效力。