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

PLoS One. 2020 Mar 26;15(3):e0228339. doi: 10.1371/journal.pone.0228339. eCollection 2020.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology*
  • Acetamides / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors*
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Immunologic Factors / pharmacokinetics
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use
  • Interferon-gamma / metabolism
  • Male
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / pathology
  • Mice
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use


  • Acetamides
  • Antineoplastic Agents
  • B7-H1 Antigen
  • BMS202
  • CD274 protein, human
  • Immunologic Factors
  • Pyridines
  • Small Molecule Libraries
  • Interferon-gamma

Grant support

This work was supported by the National Natural Science Foundation of China (grant no. 81473188), the Natural Science Foundation of Shandong Province, China (No. ZR2014HM091), Natural Science Foundation of Shandong Province (No. ZR2016HP15), and the Scientific Research Foundation of Binzhou Medical College, Shandong Province, China (No. BY2013KYQD21). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.