Department of Chemistry, Indian Institute of Technology Gandhinagar, Gujarat, India.
Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India.
Curr Top Med Chem. 2020;20(23):2070-2079. doi: 10.2174/1568026620666200731174216.
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.
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.
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.
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.
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.
抑制 DDR 通路的激酶以增强癌细胞对辐射的敏感性的重要性已得到充分证实。癌细胞利用这些激酶来生存，这导致了它们对 DNA 损伤治疗药物产生耐药性。
本文重点介绍了靶向 DDR 通路的关键介质 ATM 激酶。报道了一组新的喹啉-3-甲酰胺，作为潜在的 ATM 抑制剂。
合成了喹啉-3-甲酰胺衍生物，并进行细胞毒性测定，以分析这些分子对不同癌细胞系（如 HCT116、MDA-MB-468 和 MDA-MB-231）的影响。
合成的三种化合物对一组选定的癌细胞系表现出有希望的细胞毒性。还通过用已知的 ATM 上调剂槲皮素预处理细胞，引起 DNA 双链断裂，进行了 Western Blot 分析。SAR 研究表明，R 基团的供电子性质对于分子的毒性很重要。最后，Western-Blot 分析证实了细胞中 ATM 的下调。此外，PTEN 阴性细胞系 MDA-MB-468 对化合物的敏感性比对 PTEN 阳性细胞系 MDA-MB-231 更高。对 293T 细胞的细胞毒性研究表明，与 HCT116 相比，化合物的毒性至少低三倍。
总之，这些实验将为开发有效的和选择性的 ATM 抑制剂奠定基础，以增强癌细胞的放射和化学敏感性。
