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PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

Authors :
Hai-Bo Zhu
Ning Li
Jingwei Tian
Guangying Du
Huijuan Zhao
Liang Ye
Wenyan Wang
Zhengping Hu
Zhaoju Dong
Pengfei Yu
Source :
PLoS ONE, Vol 15, Iss 3, p e0228339 (2020), PLoS ONE
Publication Year :
2020
Publisher :
Public Library of Science (PLoS), 2020.

Abstract

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/− (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

Details

Language :
English
ISSN :
19326203
Volume :
15
Issue :
3
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.doi.dedup.....1b585b1bcc6c059d3e55da85d06c9ca8