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

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 + CD127 low/− (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.

Human and mouse PD-L1: similar molecular structure, but different druggability profiles

“…In 2019, Zhang and co-workers published their work on BMS-202 nanoparticles injected intravenously into BALB/c mice bearing mouse mammary gland 4T1 tumors ( Zhang et al., 2019 ). In 2020 Hu and collaborators claimed anti-tumor effects of BMS-202 toward B16-F10 tumors established in C57BL/6NCrl mice ( Hu et al., 2020 ). In neither of these manuscripts was the direct binding of BMS-202 to the m PD-L1 verified before moving to in vivo examination.…”

YPD-30, a prodrug of YPD-29B, is an oral small-molecule inhibitor targeting PD-L1 for the treatment of human cancer

“…2 A). YPD-29B could significantly activate PD-1/NFAT reporter-Jurkat cells in a dose-dependent manner, which was much more effective than BMS202, a known small molecular PD-L1 inhibitor 18 , 19 . Another positive control, the anti-PD-L1 neutralizing antibody, also effectively stimulated PD-1/NFAT reporter-Jurkat cells, which was comparable to YPD-29B.…”

Curcumin analog GO‐Y030 boosts the efficacy of anti‐PD‐1 cancer immunotherapy

“…In the tumor microenvironment, PD-L1 expression in B16-DF10 melanoma cells plays an important role in inhibiting tumor immunity. 16 However, we observed that GO-Y030 had no impact on the expression of PD-L1 in B16-F10 melanoma cells (Figure S3A,B). Thus, GO-Y030 inhibited L-lactate production in B16-F10 melanoma cells via metabolic changes, which repressed the immunosuppressive ability of Tregs in the tumor microenvironment.…”