Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.
J Med Chem
; 67(13): 10589-10600, 2024 Jul 11.
Article
en En
| MEDLINE
| ID: mdl-38889052
ABSTRACT
The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Antígeno B7-H1
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Proteolisis
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Antineoplásicos
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China