Twenty-nine 12 N-substituted aloperine derivatives were synthesized and screened for suppression on PD-L1 expression in H460 cells, as a continuation of our work. Systematic structural modifications led to the identification of compound 6b as the most active PD-L1 modulator. Compound 6b could significantly down-regulate both constitutive and inductive PD-L1 expression in NSCLC cells, and successively enhance the cytotoxicity of co-cultured T cells against tumor cells at the concentration of 20 µM. Also, it exhibited a moderate in vivo anticancer efficacy against Lewis tumor xenograft with a stable PK and safety profile. The mechanism study indicated that 6b mediated the degradation of PD-L1 through a proteasome pathway, rather than a lysosome route. These results provided the powerful information for cancer immunotherapy of aloperine derivatives with unique endocyclic skeleton by targeting PD-L1 to activate immune cells to kill cancer cells.
Antineoplastic Agents/pharmacology , B7-H1 Antigen/antagonists & inhibitors , Down-Regulation/drug effects , Immune Checkpoint Inhibitors/pharmacology , Proteasome Endopeptidase Complex/metabolism , Quinolizidines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Immune Checkpoint Inhibitors/chemical synthesis , Immune Checkpoint Inhibitors/chemistry , Mice , Mice, Inbred Strains , Molecular Structure , Quinolizidines/chemical synthesis , Quinolizidines/chemistry , Structure-Activity Relationship
