Feng Chunlai, Ge Yingying, Wang Siqi, Li Mengru, Chen Qiying, Dong Hangyu, Rui Mengjie
School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China.
NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China.
Pharmaceuticals (Basel). 2025 Aug 15;18(8):1209. doi: 10.3390/ph18081209.
: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have achieved clinical success but face drawbacks such as poor oral bioavailability, limited tumor penetration, and immune-related adverse events. Small-molecule inhibitors present a promising alternative that may overcome these challenges. : Here, an integrated computational framework combining ligand-based pharmacophore modeling and structure-based molecular docking was utilized to screen a comprehensive library consisting of traditional Chinese medicine-derived compounds and clinically approved drugs. The binding affinity between identified candidate compounds and PD-L1 was quantitatively assessed using bio-layer interferometry (BLI). In vitro cytotoxicity assays were conducted on A549 human lung carcinoma and LLC mouse lung carcinoma cell lines. In vivo antitumor efficacy was evaluated in LLC tumor-bearing mice through measurement of tumor growth inhibition, serum cytokine levels (IFN-γ and IL-4) by ELISA, and expression levels of IFN-γ and granzyme B (GZMB) within tumor tissues via immunohistochemistry. : In vitro, anidulafungin exhibited anti-tumor effects against both human lung cancer A549 cells and mouse Lewis lung carcinoma (LLC) tumor cells, with IC values of 170.6 µg/mL and 160.9 µg/mL, respectively. The BLI analysis revealed a dissociation constant (K) of 76.9 μM, indicating a high affinity of anidulafungin for PD-L1. In vivo, anidulafungin significantly increased serum levels of IFN-γ and IL-4 in tumor-bearing mice and elevated expression of IFN-γ and granzyme B (GZMB) in tumor tissues, confirming its immune-mediated anti-tumor effects. : Anidulafungin represents a promising small-molecule PD-L1 inhibitor, demonstrating significant anti-tumor potential via immune activation and highlighting the feasibility of repurposing approved drugs for cancer immunotherapy.
靶向PD-1/PD-L1免疫检查点的单克隆抗体已取得临床成功，但面临口服生物利用度差、肿瘤穿透性有限和免疫相关不良事件等缺点。小分子抑制剂是一种有前景的替代方案，可能克服这些挑战。
在此，利用结合基于配体的药效团建模和基于结构的分子对接的综合计算框架，对一个由中药衍生化合物和临床批准药物组成的综合文库进行筛选。使用生物层干涉术（BLI）定量评估已鉴定候选化合物与PD-L1之间的结合亲和力。对A549人肺癌和LLC小鼠肺癌细胞系进行体外细胞毒性试验。通过测量肿瘤生长抑制、用ELISA检测血清细胞因子水平（IFN-γ和IL-4）以及通过免疫组织化学检测肿瘤组织内IFN-γ和颗粒酶B（GZMB）的表达水平，在荷LLC肿瘤小鼠中评估体内抗肿瘤疗效。
在体外，阿尼芬净对人肺癌A549细胞和小鼠Lewis肺癌（LLC）肿瘤细胞均表现出抗肿瘤作用，IC值分别为170.6 µg/mL和160.9 µg/mL。BLI分析显示解离常数（K）为76.9 μM，表明阿尼芬净对PD-L1具有高亲和力。在体内，阿尼芬净显著提高荷瘤小鼠血清中IFN-γ和IL-4的水平，并提高肿瘤组织中IFN-γ和颗粒酶B（GZMB）的表达，证实其免疫介导的抗肿瘤作用。
阿尼芬净是一种有前景的小分子PD-L1抑制剂，通过免疫激活显示出显著的抗肿瘤潜力，并突出了将已批准药物重新用于癌症免疫治疗的可行性。
