Design, synthesis and biological evaluation of new dihydropyridine derivatives as PD-L1 degraders for enhancing antitumor immunity.
Bioorg Chem
; 125: 105820, 2022 08.
Article
em En
| MEDLINE
| ID: mdl-35569191
ABSTRACT
Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Di-Hidropiridinas
/
Antígeno B7-H1
Limite:
Animals
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2022
Tipo de documento:
Article