PD-1/PD-L1 inhibitor 1 (BMS-1)|1675201-83-8|安捷凯

Background

PD-1/PD-L1 inhibitor 1 is a PD-1/PD-L1 interaction inhibitor with an IC₅₀ value between 6 and 100 nM^[1]. PD-1 / PD-L1 regulates cell signaling pathways and epigenetic modifications, thereby inhibiting T cell and B cell proliferation and effector functions. Lack of tumor antigen and effective antigen presentation, abnormal activation of carcinogenic pathway, IFN- γ Signal mutation, immunosuppressive tumor microenvironment (such as regulatory T cells, myeloid derived inhibitory cells, M2 macrophages, and immunosuppressive cytokines) can lead to resistance to PD-1 / PD-L1 blockade.

PD-1/PD-L1 inhibitor 1 has been identified to be a potent and selective small molecule inhibitor blocking the interaction of programmed cell death protein 1 (PD-1) with its ligand protein (PD-L1) ^[3]. PD-1/PD-L1 inhibitor 1 was also found to act as an immunomodulator. In preclinical studies, PD-1/PD-L1 inhibitor 1 was able to block PD-1/PD-Ll interactions with an IC₅₀ value between 6 and 100 nM, which was measured by a homogenous time-resolved fluorescence (HTRF) binding assay. Thus, PD-1/PD-L1 inhibitor 1 might potentially be used for the treatment of cancer as well as infectious diseases, such as hepatitis C ^[2].

PD-1/PD-L1 inhibitor 1 +LPS treatment decreased PD-1 mRNA and protein expression in MH-S cells. BMS-1 treatment reduced TNF in LPS induced MH-S cells- α、 IL-1 β and IL-6, while IL-10 increased significantly. PD-1/PD-L1 inhibitor 1 pathway has anti apoptotic and anti-inflammatory effects on LPS stimulated MH-S cells^[3].

PD-1/PD-L1 inhibitor 1 is a small molecule inhibitor of PD-1 delivered by coated patch. After 14 days, the new intima in the PD-1/PD-L1 inhibitor 1 coated patch was thinner than the control patch. In addition, compared with the control patch, the number of PD-1, CD3, CD68, CD45 and PCNA positive cells in the PD-1/PD-L1 inhibitor 1 coated patch was also significantly reduced, with a similar number of cut caspase control and three positive cells in the PD-1/PD-L1 inhibitor 1 coated patch. These data confirm that inhibition of PD-1 can reduce the thickness of new intima and the accumulation of inflammatory cells in the new intima formed after patch angioplasty (day 14) in rats^[4].

The factors that lead to resistance to PD-1 blockade include PD-L1 expression, tumor neoantigens expression and presentation, cellular signaling pathways (PI3K, WNT, IFN-γ, MAPK), tumor microenvironment (TME) (exhausted T cell, Treg, MDSC, TAM, other chemokines), and related immune genes (IPRES). The inhibitors against target molecules are indicated, which could enhance antitumor responses in in mouse models when combined with PD-1/PD-L1 blockade^[1].

参考文献:
[1] Bai J , Gao Z , Li X , et al. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PDL1 blockade[J]. Oncotarget, 2017, 8(66).
[2] https://www. google.com/patents/WO2015034820A1
[3] Jia L, Liu K, Fei T, et al. Programmed cell death?1/programmed cell death?ligand 1 inhibitors exert antiapoptosis and antiinflammatory activity in lipopolysaccharide stimulated murine alveolar macrophages[J]. Experimental and Therapeutic Medicine, 2021, 21(4): 1-7.
[4] Bai H, Wang Z, Li M, et al. Inhibition of programmed death‐1 decreases neointimal hyperplasia after patch angioplasty[J]. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2021, 109(2): 269-278.

PD-1/PD-L1 inhibitor 1 是一种 PD-1/PD-L1 相互作用抑制剂，IC₅₀ 值介于 6 和 100 nM^[1] . PD-1/PD-L1 调节细胞信号通路和表观遗传修饰，从而抑制 T 细胞和 B 细胞的增殖和效应子功能。缺乏肿瘤抗原和有效抗原呈递、致癌通路异常激活、IFN-γ信号突变、免疫抑制性肿瘤微环境（如调节性T细胞、髓源性抑制性细胞、M2巨噬细胞和免疫抑制性细胞因子）可导致PD-耐药1 / PD-L1 阻断。

PD-1/PD-L1 抑制剂 1 已被确定为一种有效的选择性小分子抑制剂，可阻断程序性细胞死亡蛋白 1 (PD-1) 与其配体蛋白 (PD-L1) 的相互作用 ^[3].还发现 PD-1/PD-L1 抑制剂 1 可作为免疫调节剂。在临床前研究中，PD-1/PD-L1 抑制剂 1 能够阻断 PD-1/PD-Ll 相互作用，IC₅₀ 值介于 6 和 100 nM 之间，这是通过均相时间测量的-分辨荧光 (HTRF) 结合测定。因此，PD-1/PD-L1 inhibitor 1 有可能用于治疗癌症以及丙型肝炎等传染病^[2]。

PD-1/PD-L1 抑制剂 1 +LPS 处理降低了 MH-S 细胞中的 PD-1 mRNA 和蛋白质表达。 BMS-1处理降低了LPS诱导的MH-S细胞中的TNF-α、IL-1β和IL-6，而IL-10显着增加。 PD-1/PD-L1 inhibitor 1通路对LPS刺激的MH-S细胞具有抗凋亡和抗炎作用^[3]。

PD-1/PD-L1 inhibitor 1 是一种小分子 PD-1 抑制剂，通过包衣贴剂递送。 14 天后，PD-1/PD-L1 抑制剂 1 涂层贴片中的新内膜比对照贴片薄。此外，与对照贴片相比，PD-1/PD-L1抑制剂1包被的贴片中PD-1、CD3、CD68、CD45和PCNA阳性细胞的数量也明显减少，caspase被切割的数量相似PD-1/PD-L1 抑制剂 1 涂层贴片中的对照和三个阳性细胞。这些数据证实，抑制PD-1可以减少大鼠补片血管成形术（第14天）后新内膜的厚度和炎性细胞在新内膜中的积聚^[4]。

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导致PD-1阻断剂耐药的因素包括PD-L1表达、肿瘤新抗原表达和呈递、细胞信号通路（PI3K、WNT、IFN-γ、MAPK）、肿瘤微环境（TME）（耗尽的T细胞、Treg、MDSC、TAM、其他趋化因子）和相关免疫基因（IPRES）。指出了针对靶分子的抑制剂，当与 PD-1/PD-L1 阻断剂联合使用时，可以增强小鼠模型的抗肿瘤反应^[1]。

Protocol

Cell experiment [1]:
Cell lines	mouse alveolar macrophage cell line(MH-S)
Preparation Method	MH-S cells were subcultured for three times and divided into control group, lipopolysaccharide(LPS) group and LPS+ PD-1/PD-L1 inhibitor 1 (BMS-1) group. The control group was given RPMI-1640 medium equal to LPS group and LPS+BMS-1 group. When the cells in LPS group and LPS+BMS-1 group grew to 70-80% fusion, 10 ng/ml lipopolysaccharide at 37 ? stimulate in 5% CO2 humidified atmosphere at C for 24 hours, and then treat with 1 μ mol/L PD-1/PD-L1 inhibitor 1 (BMS-1) at 37 ° C for 72 hours.
Reaction Conditions	1 μmol/L PD-1/PD-L1 inhibitor 1
Applications	PD-1/PD-L1 inhibitor 1 treatment attenuated apoptosis induced by LPS exposure. The results showed that after LPS stimulation, alveolar macrophages showed a high level of PD-1 expression and increased apoptosis. After treatment with PD-1/PD-L1 inhibitor, PD-1 expression and alveolar macrophage apoptosis decreased.
参考文献: [1]. Jia L, Liu K, Fei T, et al. Programmed cell death?1/programmed cell death?ligand 1 inhibitors exert antiapoptosis and antiinflammatory activity in lipopolysaccharide stimulated murine alveolar macrophages[J]. Experimental and Therapeutic Medicine, 2021, 21(4): 1-7.