Chemical Space Navigation of Nitidine Leads to the Discovery of a Novel PD-L1 Degradation Agent by Targeting CSN5 for Enhanced Antitumor Immunity.

Expanding the chemical space of natural products is an effective strategy for discovering new drug candidates and has achieved remarkable results in activity screening. To efficiently explore the chemical space of nitidine, we developed a one-pot method to synthesize functionalized phenanthridines using commercially available or easily prepared aldehydes. Assisted by pyrrolidine and photocatalysts, the reaction proceeded under visible light at room temperature with satisfactory yields. Activity screening identified derivative e24, which reduced tumor cell PD-L1 expression more effectively than positive control JQ-1, while the prototype nitidine had minimal effects. Critically, e24 specifically targets CSN5, an essential regulatory factor, to induce PD-L1 degradation, thereby blocking the PD-1/PD-L1 interaction between T cells and tumor cells and activating the tumor immune microenvironment. In Lewis tumor and MC38 mice models, e24 exerted antitumor effects by enhancing tumor-infiltrating T-cell immunity and inhibiting the activation of immunosuppressive MDSCs and Tregs.