Rescuing TP53 from nonsense: novel triazoles for translational readthrough via optimized drug design

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Nonsense mutations create premature termination codons (PTCs), leading to non-functional truncated proteins.
• TP53 nonsense mutations occur in ~10% of TP53 alterations and are prevalent in over 50% of human cancers.
• Current therapies to restore full-length p53 protein are limited.

Purpose of the Study:

• To identify and characterize novel translational readthrough-inducing drugs (TRIDs) for restoring full-length p53 protein.
• To evaluate the efficacy of new 1,2,4-triazole-based compounds against TP53 nonsense mutations.

Main Methods:

• Utilized an optimized drug design workflow integrating in silico approaches.
• Synthesized and screened four 1,2,4-triazole compounds (IP14, IP15, IP17, IP18) with favorable ADMET profiles.
• Assessed compound efficacy in H1299 R213X cells, comparing with Ataluren and G418.

Main Results:

• All four synthesized compounds successfully restored p53 protein expression in H1299 R213X cells.
• The novel TRIDs outperformed Ataluren and matched G418 efficacy at significantly lower concentrations.
• Restored p53 protein exhibited nuclear localization and induced transcription of target genes upon genotoxic stress.

Conclusions:

• The identified 1,2,4-triazole-based TRIDs demonstrate significant therapeutic potential for treating cancers with TP53 nonsense mutations.
• These findings support the development of targeted therapies for various pathologies caused by nonsense mutations, including emerging p53-related diseases.