Abstract:
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, we focus on targeting the key mediator of the DDR pathway, the ATM kinase. We are reporting a new set of quinoline-3-carboxamides as potential inhibitors of ATM. Method: We synthesized quinoline-3-carboxamide derivatives and performed cytotoxicity assay to analyse the effect of the molecules on different cancer cell lines like HCT116, MDA-MB-468 and MDA-MB-231. Results: Three of the synthesized compounds were showing promising cytotoxicity towards a selected set of cancer cell lines. We have also performed Western Blot analysis 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.