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首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation
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Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation

机译：Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation

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摘要

Several monoclonal antibodies targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully in anticancer immunotherapy. Inherent limitations of antibody-based therapies remain, however, and alternative small-molecule inhibitors that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report the discovery of compound 17 as a bifunctional inhibitor of PD-1/PD-L1 interactions. 17 inhibits PD-1/PD-L1 interactions and promotes dimerization, internalization, and degradation of PD-L1. 17 promotes cell-surface PD-L1 internalized into the cytosol and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent pathway. Furthermore, 17 suppresses tumor growth in vivo by activating antitumor immunity. These results demonstrate that 17 targets the PD-1/PD-L1 axis and induces PD-L1 degradation.

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