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.

背景：抑制DDR途径的激酶对放射增敏癌细胞的重要性已广为人知。癌细胞利用这些激酶来维持生存，从而导致对DNA破坏性疗法的抵抗力的发展。

目的：在本文中，重点是针对DDR途径的关键介体ATM激酶。据报道，有一套新的喹啉-3-甲酰胺作为潜在的ATM抑制剂。

方法：合成喹啉-3-羧酰胺衍生物，进行细胞毒性分析，分析分子对HCT116，MDA-MB-468和MDA-MB-231等不同癌细胞系的影响。

结果：三种合成的化合物对选定的一组癌细胞系显示出有希望的细胞毒性。Western Blot分析还通过用槲皮素（一种已知的ATM上调剂）对细胞进行预处理来引起DNA双链断裂来进行。SAR研究表明，R基团的供电子性质对于分子有毒至关重要。最后，蛋白质印迹分析证实了细胞中ATM的下调。另外，与PTEN阳性细胞系MDA-MB-231相比，PTEN阴性细胞系MDA-MB-468对化合物更敏感。针对293T细胞的细胞毒性研究表明，与HCT116相比，该化合物的毒性至少低三倍。

结论：总之，这些实验将为有效和选择性的ATM抑制剂向癌细胞的放射敏化和化学敏化发展奠定基础。