Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors

[Display omitted] •Ⅲ-4 directly binds to PD-L1 to block the interaction between PD-1/PD-L1.•Ⅲ-4 relieves the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ.•Ⅲ-5, an ester prodrug derived from Ⅲ-4, demonstrates significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model. A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC50 value of 2.9 nM and a KD value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3+ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.