NSCLC is marked by low survival and resistance to platinum-based chemotherapy. The XPG endonuclease has emerged as a promising biomarker for predicting the prognosis of cisplatin-treated patients and its downregulation having been reported to increase cisplatin efficacy. This study presents an integrated strategy for identifying small molecule inhibitors of XPG to improve cisplatin therapy in NSCLC. A structure-based virtual screening approach was adopted, including a structural and physicochemical analysis of the protein, and a library of small molecules with reported inhibitory activities was retrieved. This analysis identified Lys84 as a crucial residue for XPG activity by targeting its interaction with DNA. After molecular docking and virtual screening calculations, 61 small molecules were selected as potential XPG inhibitors, acquired from the ChemBridge database and then validated in H1299 cells, a NSCLC cell line exhibiting the highestERCC5expression. The MTS assay was performed as a first screening approach to determine whether these potential inhibitors could enhance cisplatin-induced cytotoxicity. Overall, among the eight compounds identified as the most promising, three of them revealed to significantly increase the impact of cisplatin. The inherent cytotoxicity of these compounds was further investigated in a non-tumoral lung cell line (BEAS-2B cells), which resulted in the identification of two non-cytotoxic candidates to be used in combination with cisplatin in order to improve its efficacy in NSCLC therapy.
非小细胞肺癌（NSCLC）以低生存率及对铂类化疗耐药为特征。XPG核酸内切酶已成为预测顺铂治疗患者预后的有前景的生物标志物，其表达下调已被证实可增强顺铂疗效。本研究提出了一种整合策略，旨在通过筛选XPG小分子抑制剂以改善NSCLC的顺铂治疗效果。采用基于结构的虚拟筛选方法，包括对蛋白质进行结构与理化性质分析，并检索具有已报道抑制活性的小分子化合物库。分析发现靶向XPG与DNA相互作用的关键残基Lys84对XPG活性至关重要。通过分子对接与虚拟筛选计算，从ChemBridge数据库中筛选出61个潜在XPG抑制剂，并在ERCC5表达水平最高的NSCLC细胞系H1299中进行验证。采用MTS法作为初筛手段，评估这些潜在抑制剂能否增强顺铂诱导的细胞毒性。最终筛选出的八个最具潜力化合物中，有三个能显著增强顺铂作用效果。进一步在非肿瘤肺细胞系（BEAS-2B细胞）中评估这些化合物的固有细胞毒性，最终鉴定出两个无细胞毒性的候选化合物，可与顺铂联用以提升NSCLC治疗疗效。
肿瘤(癌症)患者之家