Discovery of Novel d‑(+)-Biotin-Conjugated Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors for Targeted Cancer Immunotherapy

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 IC50 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