AI Article Synopsis
- Blocking the PD-1/PD-L1 interaction has proven effective in cancer therapy, but issues like low response rates and side effects limit the use of anti-PD-1/PD-L1 antibodies.
- The discovery of a new small-molecule inhibitor of PD-L1 shows promise, as it disrupts the PD-L1/PD-1 interaction, induces PD-L1 dimerization and internalization, and enhances tumor-targeting immune cell activity.
- This new inhibitor demonstrated significant tumor growth inhibition in lung and colorectal cancer models, effectively clearing some tumor cells in colorectal cases and promoting T-cell activation while reversing the negative tumor environment.
Article Abstract
Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of , an innovative small-molecule inhibitor of PD-L1. , effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. , significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of as an alternative ICB therapeutic strategy.
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| http://dx.doi.org/10.1021/acs.jmedchem.2c01801 | DOI Listing |
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