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PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice
- 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.
- Subjects :
- 0301 basic medicine
Male
Melanomas
Pyridines
Physiology
Melanoma, Experimental
Cancer Treatment
Pharmacology
B7-H1 Antigen
Mice
White Blood Cells
0302 clinical medicine
Animal Cells
Acetamides
Cellular types
Medicine and Health Sciences
Cytotoxic T cell
IL-2 receptor
Enzyme-Linked Immunoassays
Multidisciplinary
biology
Chemistry
Organic Compounds
Regulatory T cells
Small molecule
Body Fluids
Blood
Oncology
030220 oncology & carcinogenesis
Physical Sciences
Engineering and Technology
Medicine
Anatomy
Research Article
Biotechnology
Cell biology
Blood cells
CD3
Immune Cells
Science
Immunology
T cells
Antineoplastic Agents
Cytotoxic T cells
Bioengineering
Research and Analysis Methods
Blood Plasma
Small Molecule Libraries
03 medical and health sciences
Interferon-gamma
Pharmacokinetics
PD-L1
Animals
Humans
Immunologic Factors
Immunoassays
Cell Proliferation
Biology and life sciences
Organic Chemistry
Chemical Compounds
Correction
Cancers and Neoplasms
In vitro
030104 developmental biology
Small Molecules
Drug Design
biology.protein
Immunologic Techniques
CD8
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 15
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....1b585b1bcc6c059d3e55da85d06c9ca8