Structure-activity relationship and biological evaluation of 12 N-substituted aloperine derivatives as PD-L1 down-regulatory agents through proteasome pathway
| Autor: | Ying–Hong Li, Yu-Long Shi, Yue–Ying Dou, Zhi–Hao Guo, Kun Wang, Qing–Xuan Zeng, Xin–Tong Zhang, Dan–Qing Song, Hongbin Deng, Na Zhang, Xin Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
Proteasome Endopeptidase Complex
Quinolizidines medicine.medical_treatment Down-Regulation Antineoplastic Agents Mice Inbred Strains Biochemistry B7-H1 Antigen Mice Structure-Activity Relationship Immune system Cancer immunotherapy In vivo Lysosome Drug Discovery medicine Structure–activity relationship Animals Humans Cytotoxicity Molecular Biology Immune Checkpoint Inhibitors Cells Cultured Cell Proliferation Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry medicine.anatomical_structure Proteasome Cancer cell Cancer research Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic chemistry. 117 |
| ISSN: | 1090-2120 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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