Design, Synthesis, and Biological Evaluation of Chroman Derivatives as PD-1/PD-L1 Antagonists.
J Chem Inf Model
; 64(12): 4877-4896, 2024 Jun 24.
Article
em En
| MEDLINE
| ID: mdl-38856697
ABSTRACT
Programmed death-ligand 1 (PD-L1) has emerged as a promising therapeutic target for various cancers due to its crucial role in promoting tumor immune evasion. Here, we report a novel class of chroman-like small-molecule PD-L1 inhibitors exhibiting significant activity in inhibiting the PD-1/PD-L1 interaction. Employing a "ring-close" strategy for conformational restriction, we have achieved compound C27, which demonstrates superior PD-1/PD-L1 inhibitory activity compared to the positive control. Molecular dynamics simulation and binding free energy calculation predict that (R)-C27 with inhibitory activity surpassed (S)-C27. The experimental results from bioassay and X-ray structural analysis corroborate these findings. All these results collectively indicate that (R)-C27 is a promising lead compound deserving further exploration.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Cromanos
/
Antígeno B7-H1
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Receptor de Morte Celular Programada 1
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article