Structure-activity relationship and biological evaluation of 12 N-substituted aloperine derivatives as PD-L1 down-regulatory agents through proteasome pathway.
Bioorg Chem
; 117: 105432, 2021 12.
Article
en En
| MEDLINE
| ID: mdl-34678602
ABSTRACT
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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
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Complejo de la Endopetidasa Proteasomal
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Quinolizidinas
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Antígeno B7-H1
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Inhibidores de Puntos de Control Inmunológico
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Antineoplásicos
Límite:
Animals
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Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article