Issue 26, 2024

Design and synthesis of nucleic acid nano-environment interactome-targeting small molecule PROTACs and their anticancer activity

Abstract

Targeted protein degradation through PROteolysis TArgeting Chimeras (PROTACs) is a relatively new modality in cellular interventions. The minimum requirement for PROTACs to function is forming a tertiary complex of the protein of interest (POI), E3 ligase, and the molecular glue PROTAC. Here, we propose a new approach to modulate the nano-environment interactome of a non-protein target through a plausible quaternary complex of interactome–biomolecule of interest (BOI)–PROTAC and E3 ligase. We report nucleic acid-targeting PROTAC (NA-TAC) molecules by conjugating DNA-binding and E3 ligase ligands. We demonstrate that NA-TACs can target the G-quadruplex DNA and induce elevated DNA damage and cytotoxicity compared to the conventional G-quadruplex binding ligands. Our new class of NA-TACs lays the foundation for small molecule-based non-protein targeting PROTACs for interactome and nanoenvironment mapping and nucleic acid-targeted precision medicines.

Graphical abstract: Design and synthesis of nucleic acid nano-environment interactome-targeting small molecule PROTACs and their anticancer activity

Supplementary files

Article information

Article type
Paper
Submitted
12 Marts 2024
Accepted
29 Maijs 2024
First published
31 Maijs 2024

Nanoscale, 2024,16, 12502-12509

Design and synthesis of nucleic acid nano-environment interactome-targeting small molecule PROTACs and their anticancer activity

S. Tanga, A. Karmakar, A. Hota, P. Banerjee and B. Maji, Nanoscale, 2024, 16, 12502 DOI: 10.1039/D4NR01006J

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