PD-1/PD-L1 inhibitor 1 (BMS-1)
(Synonyms: BMS-1) 目录号 : GC15142
A PD-1/PD-L1 interaction inhibitor
Cas No.:1675201-83-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
mouse alveolar macrophage cell line(MH-S) |
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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. |
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Reaction Conditions |
1 µmol/L PD-1/PD-L1 inhibitor 1 |
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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. |
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References: [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. |
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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].
References:
[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]。
\n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]。
| Cas No. | 1675201-83-8 | SDF | |
| 别名 | BMS-1 | ||
| 化学名 | (S)-1-(2,6-dimethoxy-4-((2-methyl-[1,1'-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid | ||
| Canonical SMILES | O=C([C@H]1N(CC2=C(OC)C=C(OCC3=CC=CC(C4=CC=CC=C4)=C3C)C=C2OC)CCCC1)O | ||
| 分子式 | C29H33NO5 | 分子量 | 475.58 |
| 溶解度 | ≥ 5.98mg/mL in DMSO with ultrasonic and warming | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1027 mL | 10.5135 mL | 21.027 mL |
| 5 mM | 0.4205 mL | 2.1027 mL | 4.2054 mL |
| 10 mM | 0.2103 mL | 1.0513 mL | 2.1027 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages
J Exp Clin Cancer Res2022 Jan 3;41(1):1.PMID: 34980222DOI: 10.1186/s13046-021-02201-4
Background: Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity.
Methods: A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson's trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student's t-test for two-group comparisons, and one-way ANOVA followed by Student-Newman-Keul test for multiple-group comparisons.
Results: We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis.
Conclusions: Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.
PD-1/PD-L1 inhibition promotes hepatic regeneration in small-for-size liver following extended hepatectomy
Cytokine2022 Nov;159:156017.PMID: 36054963DOI: 10.1016/j.cyto.2022.156017
Background: Small-for-size syndrome following liver surgery is characterized by compromised liver regeneration. Liver macrophages play key roles in initiating liver regeneration, and modulation of the immune microenvironment through macrophages may accelerate liver regeneration. In our current study, we aimed to explore the involvement of innate immunity after extended hepatectomy in rats and humans, and to test the effect of immunity modulation on small-for-size liver regeneration in rats.
Methods: Serum programmed cell death protein ligand 1 (PD-L1) was measured after major hepatectomy and minor hepatectomy in humans and rats. Liver regeneration in rats was assessed using liver-to-body weight ratio and kinetic growth rate, antigen Ki67 and proliferating cell nuclear antigen (PCNA), and macrophage polarization was assessed by inducible nitric oxide synthase (iNOS), cluster of differentiation protein 163 (CD163) expression by immunohistochemistry (IHC) and iNOS/CD163 ratio. Rat hepatocyte BRL or human hepatocyte LO2 were co-cultured with rat bone marrow-derived macrophages or human macrophages THP-1. BMS-1 or Nivolumab were used to block programmed cell death protein 1 (PD-1)/PD-L1 in vitro and in vivo.
Results: PD-L1 expressions were significantly higher following major hepatectomy compared to minor resection in both humans and rats; compromised liver regeneration after extended hepatectomy in rats was associated with PD-L1 upregulation and M2 macrophage polarization. M1 macrophages increased proliferation of hepatocytes through interleukin-6 (IL-6), and M2 macrophages decreased hepatocyte proliferation; blocking PD-1/PD-L1 reversed the effect of M2 macrophages on the survival of hepatocytes in vitro and promoted liver growth in rats through M1 macrophage polarization.
Conclusion: Compromised hepatic regeneration following extended hepatectomy is characterized by M2 macrophage polarization and upregulated PD-L1 expression. Blocking PD-1/PD-L1 may enhance small-for-size liver regeneration by inducing M1 macrophage polarization.
Programmed death-1 mediates venous neointimal hyperplasia in humans and rats
Aging (Albany NY)2021 Jun 24;13(12):16656-16666.PMID: 34170847DOI: 10.18632/aging.203185
Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.
Inhibition of programmed death-1 decreases neointimal hyperplasia after patch angioplasty
J Biomed Mater Res B Appl Biomater2021 Feb;109(2):269-278.PMID: 32770622DOI: 10.1002/jbm.b.34698
Neointimal hyperplasia remains an obstacle after vascular interventions. Programmed death-1 (PD-1) antibody treatment decreases tumor cell proliferation and secretion of inflammatory factors, and several antineoplastic drugs show efficacy against neointimal hyperplasia. We hypothesized that inhibition of PD-1 inhibits neointimal hyperplasia in a rat patch angioplasty model. In a rat aorta patch angioplasty model, four groups were compared: the control group without treatment, a single dose of humanized PD-1 antibody (4 mg/kg) injected immediately after patch angioplasty, PD-1 antibody-coated patches, and BMS-1 (PD-1 inhibitor)-coated patches. Patches were harvested (Day 14) and analyzed. After patch angioplasty, PD-1-positive cells were present. Inhibition of PD-1 using both intraperitoneal injection of humanized PD1 antibody as well as using patches coated with humanized PD1 antibody significantly decreased neointimal thickness (p = 0.0199). There were significantly fewer PD-1 (p = 0.0148), CD3 (p = 0.0072), CD68 (p = 0.0001), CD45 (p = 0.001), and PCNA (p < 0.0001)-positive cells, and PCNA/α-actin dual positive cells (p = 0.0005), in the treated groups. Patches coated with BMS-1 showed similarly decreased neointimal thickness and accumulation of inflammatory cells. Inhibition of PD-1 using PD-1 antibody or its inhibitor BMS-1 can significantly decrease neointimal thickness in vascular patches. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit neointimal hyperplasia.
Immune checkpoint programmed death-1 mediates abdominal aortic aneurysm and pseudoaneurysm progression
Biomed Pharmacother2021 Oct;142:111955.PMID: 34339918DOI: 10.1016/j.biopha.2021.111955
Purpose: The causes and pathogenetic mechanisms underlying abdominal aortic aneurysms (AAAs) and pseudoaneurysms are not fully understood. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease AAA and pseudoaneurysm formation in mouse and rat models.
Methods: Human AAA samples were examined in conjunction with an adventitial calcium chloride (CaCl2) application mouse model and an aortic patch angioplasty rat model. Single-dose PD-1 antibody (4 mg/kg) or BMS-1 (PD-1 inhibitor-1) (1 mg/kg) was administered by intraperitoneal (IP) or intraluminal injection. In the intramural injection group, PD-1 antibody was injected after CaCl2 incubation. The rats were divided into three groups: (1) the control group was only decellularized without other special treatment, (2) the PD-1 antibody-coated patch group, and (3) the BMS-1 coated patch group. Patches implanted in the rat abdominal aorta were harvested on day 14 after implantation and analyzed.
Results: Immunohistochemical analysis showed PD-1-positive cells, PD-1 and CD3, PD-1 and CD68, and PD-1 and α-actin co-expressed in the human AAA samples. Intraperitoneal (IP) injection or intraluminal injection of PD-1antibody/BMS-1 significantly inhibited AAA progression. PD-1 antibody and BMS-1 were each successfully conjugated to decellularized rat thoracic artery patches, respectively, by hyaluronic acid. Patches coated with either humanized PD-1 antibody or BMS-1 can also inhibit pseudoaneurysm progression and inflammatory cell infiltration.
Conclusion: PD-1 pathway inhibition may be a promising therapeutic strategy for inhibiting AAA and pseudoaneurysm progression.