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Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

Nat Commun. 2021-02; 
Jang-June Park, Emily P Thi, Victor H Carpio, Yingzhi Bi, Andrew G Cole, Bruce D Dorsey, Kristi Fan, Troy Harasym, Christina L Iott, Salam Kadhim, Jin Hyang Kim, Amy C H Lee, Duyan Nguyen, Bhavna S Paratala, Ruiqing Qiu, Andre White, Damodharan Lakshminarasimhan, Christopher Leo, Robert K Suto, Rene Rijnbrand, Sunny Tang, Michael J Sofia, Chris B Moore
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摘要

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and pro... More

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