The PD‐1/PD‐L1 binding inhibitor BMS‐202 suppresses the synthesis and secretion of gonadotropins and enhances apoptosis via p38 MAPK signaling pathway

Abstract

To determine whether BMS‐202 can disrupt the pituitary gland and reproductive system. BMS‐202 (2.5 mg/kg) was injected intraperitoneally into adult female mice every 96 h for four times. Real‐time polymerase chain reaction, western blotting, double immunofluorescence staining and radioimmunoassays (RIA) were used to study the expressions of programmed death receptor 1 (PD‐1) and programmed death ligand 1 (PD‐L1), and detect changes after BMS‐202 treatment in the mouse pituitary gland. PD‐1 and PD‐L1 were expressed in the mouse pituitary gland. Further functional studies demonstrated that BMS‐202 inhibited the synthesis and secretion of gonadotropins and prolonged the estrous cycle in mice. Moreover, the increases of cleaved caspase3 (c‐caspase3) protein level both in vivo and in vitro indicated that BMS‐202 induced apoptosis. Additionally, the effects of BMS‐202 on follicle‐stimulating hormone and luteinizing hormone mRNA levels were blocked by a p38 MAPK inhibitor. Of note, the inhibition of p38 MAPK pathway decreased the apoptosis induced by BMS‐202. BMS‐202, as a drug which inhibits the formation of the PD‐1/PD‐L1 complex, disrupts the normal function of the pituitary gland. Importantly, the results confirmed the potential insecurity of BMS‐202 in the pituitary gland and provided data to support the evaluation of its clinical application.

Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma

“…Taken together, these results suggest that BMS-202 has a crucial function in metabolic reprogramming by modulating PD-L1/AKT/BCAT1 signaling pathways. Our results are complementary to those of previous studies that have identified BMS-202-associated signaling pathways [34,35] . Additionally, for the first time, we report that BMS-202 metabolic genes at the metabolism level are associated with clinical consequences in patients with glioma, including the length of patient survival times.…”

Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma

“…Another important finding in our study was that BMS-202 significantly induced changes in the expression of BCAT1/2 protein and mRNA in GBM cells, confirming its role in remodeling the metabolic landscape. Taken together, these results suggest that BMS-202 is critical in reprogramming the cell metabolism by modulating the PD-L1/AKT/BCAT1 signaling pathways, which shed novel insights into previous BMS-202-associated signaling pathways [ 32 , 33 ].…”

Development of small molecule drugs targeting immune checkpoints

“…The antitumor effects of BMS-202 have been verified in melanoma and mouse models, while inhibition of PD-1/PD-L1 binding by BMS-202 successfully rescues the suppressed IFN-γ production in T cells 72 . In addition, BMS-202 has the advantages of high bioavailability and low toxicity 73 – 75 . In addition, a series of derivatives of benzo[d]isothiazole have been developed using BMS-202 as a starting point, exhibiting a superior effect in inhibiting the PD-1/PD-L1 interaction and lower cytotoxicity to T cells compared to BMS-202 76 , 77 .…”