Novel Selenium-Containing Small Molecule PD-L1 Inhibitors: Design, Synthesis, and Evaluation of the Antitumor Activity

Novel selenium-containing small molecule PD-L1 inhibitors were designed and synthesized for the first time to explore their potential as antitumor agents. By computer-aided structural optimization, HTRF and SPR techniques, compound SA13 was identified as the most potent blocker of the PD-1/PD-L1 interaction, exhibiting an IC 50 value of 5.2 ± 0.5 nM, a K D value of 9.06 ± 1.25 nM, respectively. Study on the SA13 /hPD-L1 cocrystal structure (2.9 Å) revealed a unique selenomethyl-involved binding mode, which may interpret its superior inhibitory activity compared to other analogs. Cell-based assays showed that SA13 can mediate the internalization of PD-L1 and strongly block hPD-1 and hPD-L1 interaction, demonstrating its effectiveness in biological events. Notably, in the Hu-PD-L1 MC38 mouse model, SA13 significantly inhibited tumor growth, with a tumor growth inhibition (TGI) rate of 77.79% (60 mg/kg, administrated intragastrically) with no observable toxicity. These data indicate that SA13 is a promising and safe novel antitumor agent worthy of further development.