发现新型 d-(+)-生物素偶联间苯二酚二苄醚基 PD-L1 抑制剂用于靶向癌症免疫治疗

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, SWS1 exhibited the highest anti-PD-1/PD-L1 activity with an IC 50 of 1. 8 nM.

In addition, SWS1 dose-dependently promoted tumor cell death in a HepG2/Jurkat cell co-culture model.

Importantly, SWS1 displayed high antitumor efficacy in a B16-F10 mouse model with tumor growth inhibition of 66. 1%, which was better than that of P18 (44. 3%).

Furthermore, SWS1 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 SWS1 in tumors (404. 1 ng/mL). Lastly, the safety profiles of SWS1 were better (e. g. , less immune-mediated colitis) than those of P18 , 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.