Institute of Microbial Chemistry, Shinagawa-ku, Tokyo 141-0021, Japan.
Gakubunkan Institute of Physiology and Medicine, Jobu University, Takasaki-shi, Isesaki 370-1393, Japan.
Biomolecules. 2024 Sep 23;14(9):1197. doi: 10.3390/biom14091197.
We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by variant III () transduction. One of its targets has been shown to be NDUFA12 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex Subunit 12), a component protein of oxidative phosphorylation complex I. In this report, we compared the growth inhibitory activity of Ertredin with its methylated analogue 7MeERT (3-(2-amino-5-bromophenyl)-7-methylquinoxalin-2(1H)-one) on human cancer cells. 7MeERT induced the inhibition of the proliferation of various cancer cells similarly to Ertredin and showed higher activity in glioblastoma cells, A431 cells overexpressing (wild type), and multiple myeloma cells. Molecular docking analysis and a Cellular Thermal Shift Assay (CETSA) suggested that 7MeERT binds to NDUFA12 similarly to Ertredin. The binding of 7MeERT and Ertredin to NDUFA12 in glioblastoma was further supported by the inhibition of the oxygen consumption rate. These results suggest that 7MeERT also binds to NDUFA12, inhibits oxidative phosphorylation, and has a higher anti-cancer cell growth inhibitory activity than Ertredin.
我们之前已经确定 Ertredin（3-（2-氨基-5-溴苯基）喹喔啉-2（1H）-酮）是一种能抑制由变异 III ()转导诱导的 NIH3T3 细胞的 3D 球体形成和肿瘤发生的化合物。其靶标之一已被证明是 NADH 脱氢酶（泛醌）1 亚基复合物亚单位 12（NDUFA12），这是氧化磷酸化复合物 I 的组成蛋白。在本报告中，我们比较了 Ertredin 与其甲基化类似物 7MeERT（3-（2-氨基-5-溴苯基）-7-甲基喹喔啉-2（1H）-酮）对人类癌细胞的生长抑制活性。7MeERT 诱导各种癌细胞的增殖抑制类似于 Ertredin，并且在神经胶质瘤细胞、过表达 （野生型）的 A431 细胞和多发性骨髓瘤细胞中显示出更高的活性。分子对接分析和细胞热转移分析（CETSA）表明，7MeERT 与 Ertredin 相似地与 NDUFA12 结合。7MeERT 和 Ertredin 在神经胶质瘤中与 NDUFA12 的结合进一步得到了氧消耗率抑制的支持。这些结果表明，7MeERT 也与 NDUFA12 结合，抑制氧化磷酸化，并且具有比 Ertredin 更高的抗癌细胞生长抑制活性。
