Discovery of a novel, potent and selective small-molecule inhibitor of PD-1/PD-L1 interaction with robust in vivo anti-tumour efficacy.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

B7-H1 Antigen*/antagonists & inhibitors ; Neoplasms*/drug therapy ; Programmed Cell Death 1 Receptor*/antagonists & inhibitors; Animals ; Immunotherapy ; Mice ; Tumor Microenvironment

Background and Purpose: PD-1/PD-L1 antibodies have achieved great success in clinical treatment. However, monoclonal antibody drugs also have challenges, such as high manufacturing costs, poor diffusion, low oral bioavailability and limited penetration into tumour tissue. The development of small-molecule inhibitors of PD-1/PD-L1 interaction represents a promising perspective to overcome the above challenges in cancer immunotherapy.
Experimental Approach: We explored structural activity relationships and used biochemical assays to generate a lead compound (ZE132). CD8+ T-cells killing assay and Ifng expression assay were used to verify the in vitro cellular activity of ZE132. Off-target study was performed to verify the selectivity. Syngeneic mouse models were used to verify the in vivo activity of ZE132 in tumour immune microenvironment (TIME). We also performed pharmacokinetics profiling in mice and The Cancer Genome Atlas database analysis.
Key Results: ZE132 can effectively inhibit the PD-1/PD-L1 interactions in vitro, and it has a potent affinity to PD-L1. ZE132 shows robust anti-tumour effects in vivo, better than anti-PD-1 antibody. In the analysis of TIME, we found that ZE132 treatment promotes cytotoxic T-cell tumour infiltration and induces IL-2 expression. In addition, ZE132 elicits strong inhibitory effects on the mRNA expression of TGF-β, which may serve as a potential biomarker to predict responsiveness to PD-1/PD-L1 immunotherapies.
Conclusion and Implications: We identified a new lead compound ZE132 targeting PD-1/PD-L1 interactions, not only showing favourable drug-like properties in vitro and in vivo but also showing the advantage of overcoming the barrier of TIME compared to anti-PD-1 antibody.
(© 2021 The British Pharmacological Society.)

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18431907100 Science and Technology Commission of Shanghai Municipality; 2018ZX09711002-005 National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China; 2018ZX09711002-004-010 National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China; 18JC1413800 Shanghai Science and Technology Commission; 20430713600 Shanghai Science and Technology Commission; 18ZR1403900 Shanghai Science and Technology Commission; 81872724 National Natural Science Foundation of China; 81872895 National Natural Science Foundation of China; 82073682 National Natural Science Foundation of China

Keywords: PD-1/PD-L1; TGF-β; immunotherapy; tumour immune microenvironment

0 (B7-H1 Antigen)
0 (Programmed Cell Death 1 Receptor)

Date Created: 20210326 Date Completed: 20210705 Latest Revision: 20220531

20231215

10.1111/bph.15457

33768523