Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

中文翻译：

无嘌呤/无嘧啶核酸内切酶 1 (APE1) 在碱基切除修复 (BER) 途径中起关键作用，该途径负责切除无嘌呤位点 (AP 位点)。在非小细胞肺癌 (NSCLC) 中，APE1 高度表达并与患者预后不良相关。APE1 的抑制可能导致细胞中未修复的 DNA 损伤的积累。因此，APE1被视为恶性肿瘤的重要标志物，可作为开发抗肿瘤药物的有效靶点。在本研究中，我们利用 APE1 蛋白的三维结构对小分子文库进行了高通量虚拟筛选。使用 AP 位点裂解试验和细胞存活试验，我们确定了一种小分子化合物 NO.0449-0145，作为 APE1 抑制剂。用 NO.0449-0145 处理诱导 DNA 损伤，NSCLC 细胞系 A549 和 NCI-H460 中的细胞凋亡、细胞焦亡和坏死性凋亡。该抑制剂还能够阻止 NCI-H460 小鼠模型中的癌症进展。此外，NO.0449-0145 克服了 NSCLC 细胞系中对顺铂和厄洛替尼的耐药性。这些发现强调了 APE1 作为 NSCLC 治疗靶点的重要性，并为开发靶向关键 DNA 修复蛋白的小分子药物用于治疗 NSCLC 和其他癌症提供了范例。