Background:
The importance of inhibiting the kinases of the DDR pathway for radiosensitizing
cancer cells is well established. Cancer cells exploit these kinases for their survival, which leads to
the development of resistance towards DNA damaging therapeutics.
Objective:
In this article, the focus is on targeting the key mediator of the DDR pathway, the ATM
kinase. A new set of quinoline-3-carboxamides, as potential inhibitors of ATM, is reported.
Methods:
Quinoline-3-carboxamide derivatives were synthesized and cytotoxicity assay was performed
to analyze the effect of molecules on different cancer cell lines like HCT116, MDA-MB-468, and
MDA-MB-231.
Results:
Three of the synthesized compounds showed promising cytotoxicity towards a selected set of
cancer cell lines. Western Blot analysis was also performed by pre-treating the cells with quercetin, a
known ATM upregulator, by causing DNA double-strand breaks. SAR studies suggested the importance
of the electron-donating nature of the R group for the molecule to be toxic. Finally, Western-Blot analysis
confirmed the down-regulation of ATM in the cells. Additionally, the PTEN negative cell line,
MDA-MB-468, was more sensitive towards the compounds in comparison with the PTEN positive cell
line, MDA-MB-231. Cytotoxicity studies against 293T cells showed that the compounds were at least
three times less toxic when compared with HCT116.
Conclusion:
In conclusion, these experiments will lay the groundwork for the evolution of potent and
selective ATM inhibitors for the radio- and chemo-sensitization of cancer cells.
