Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, P. R. China.
The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, Zhejiang 323000, China.
J Med Chem. 2023 Aug 10;66(15):10364-10380. doi: 10.1021/acs.jmedchem.3c00479. Epub 2023 Jul 21.
In this work, we rationally designed, synthesized, and evaluated a series of novel d-(+)-biotin-conjugated PD-L1 inhibitors for targeted cancer therapy. Among them, exhibited the highest anti-PD-1/PD-L1 activity with an IC of 1.8 nM. In addition, dose-dependently promoted tumor cell death in a HepG2/Jurkat cell co-culture model. Importantly, displayed high antitumor efficacy in a B16-F10 mouse model with tumor growth inhibition of 66.1%, which was better than that of (44.3%). Furthermore, exerted antitumor effects by increasing the number of tumor-infiltrating lymphocytes and reducing the expression of PD-L1 in tumor tissues. Moreover, tissue distribution studies revealed a substantial accumulation of in tumors (404.1 ng/mL). Lastly, the safety profiles of were better (e.g., less immune-mediated colitis) than those of , indicating the advantages of biotin-enabled tumor targeting capability. Taken together, our results suggest that these novel tumor-targeted PD-L1 inhibitors are worthy of further investigation as potential anticancer agents for targeted cancer immunotherapy.
在这项工作中，我们合理设计、合成并评价了一系列新型的 d-(+)-生物素缀合的 PD-L1 抑制剂，用于靶向癌症治疗。其中，化合物 表现出最高的抗 PD-1/PD-L1 活性，IC 为 1.8 nM。此外，在 HepG2/Jurkat 细胞共培养模型中， 呈剂量依赖性促进肿瘤细胞死亡。重要的是， 在 B16-F10 小鼠模型中显示出高抗肿瘤疗效，肿瘤生长抑制率为 66.1%，优于 （44.3%）。此外， 通过增加肿瘤浸润淋巴细胞的数量和降低肿瘤组织中 PD-L1 的表达发挥抗肿瘤作用。此外，组织分布研究表明， 在肿瘤中有大量的 （404.1 ng/mL）蓄积。最后， 的安全性更好（例如，免疫介导的结肠炎较少），表明生物素介导的肿瘤靶向能力具有优势。总之，我们的研究结果表明，这些新型的肿瘤靶向 PD-L1 抑制剂作为潜在的癌症免疫治疗靶向药物值得进一步研究。
