Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 16, Pages -Publisher
MDPI
DOI: 10.3390/ijms22168737
Keywords
NMR spectroscopy; CD; G-quadruplex; molecular modeling; PARP1 inhibitors; fluorescence titration; PARP1 promoter; dual-targeting
Funding
- PIANO DI SOSTEGNO ALLA RICERCA 2020-Linea 2 azione B (DEFENS)
- Spanish Ministerio de Ciencia e Innovacion [PID2019-107158GB-I00]
- Autonomous Catalan government [2017SGR114]
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DNA repair inhibitors, particularly PARP1 inhibitors, have emerged as a new approach in cancer chemotherapy. Recent studies have shown that certain PARP1 inhibitors can form defined complexes with G-quadruplex structures within the PARP1 gene promoter, suggesting the potential development of better binders to inhibit the enzyme activity.
DNA repair inhibitors are one of the latest additions to cancer chemotherapy. In general, chemotherapy produces DNA damage but tumoral cells may become resistant if enzymes involved in DNA repair are overexpressed and are able to reverse DNA damage. One of the most successful drugs based on modulating DNA repair are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. Several PARP1 inhibitors have been recently developed and approved for clinical treatments. We envisaged that PARP inhibition could be potentiated by simultaneously modulating the expression of PARP 1 and the enzyme activity, by a two-pronged strategy. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter has been recently identified. In this study, we explored the potential binding of clinically approved PARP1 inhibitors to the G-quadruplex structure found at the gene promoter region. The results obtained by NMR, CD, and fluorescence titration confirmed by molecular modeling demonstrated that two out the four PARP1 inhibitors studied are capable of forming defined complexes with the PARP1 G-quadruplex. These results open the possibility of exploring the development of better G-quadruplex binders that, in turn, may also inhibit the enzyme.
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