PD-1/ PD-L1

PD-1- in -17是CA-170的类似物，是一种程序性细胞死亡-1 (PD-1)抑制剂。

[1]. 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators. WO2015033301A1.

CA-170 is a selective, small molecule inhibitor of PD-L1. PD-L1/PD-L2/VISTA Antagonist CA-170 is an orally bioavailable small molecule inhibitor of the immune checkpoint regulatory proteins programmed cell death ligand-1 (PD-L1; B7-H1; CD274), PD-L2, and V-domain immunoglobulin (Ig) suppressor of T-cell activation (VISTA; programmed death 1 homolog; PD1H; PD-1H), with potential negative immune checkpoint regulatory and antineoplastic activities. Upon oral administration, PD-L1/PD-L2/VISTA antagonist CA-170 targets and binds to PD-L1, PD-L2 and VISTA. This inhibits PD-L1/PD-L2/VISTA-mediated signaling, abrogates the PD-L1-, PD-L2- and VISTA-induced suppression of T-lymphocyte immune responses, enhances cytotoxic T-cell proliferation and activation against tumor cells, increases cytokine production by T-cells, and inhibits tumor cell growth. PD-L1, PD-L2 and VISTA, negative checkpoint molecules of immune activation, play key roles in the suppression of T-cell functions.

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CA-170 is currently the only small-molecule modulator in clinical trials targeting PD-L1 and VISTA proteins - important negative checkpoint regulators of immune activation. The reported therapeutic results to some extent mimic those of FDA-approved monoclonal antibodies overcoming the limitations of the high production costs and adverse effects of the latter. However, no conclusive biophysical evidence proving the binding to hPD-L1 has ever been presented. Using well-known in vitro methods: NMR binding assay, HTRF and cell-based activation assays, we clearly show that there is no direct binding between CA-170 and PD-L1. To strengthen our reasoning, we performed control experiments on AUNP-12 - a 29-mer peptide, which is a precursor of CA-170. Positive controls consisted of the well-documented small-molecule PD-L1 inhibitors: BMS-1166 and peptide-57.[Molecules. 2019 Aug 1;24(15):2804.]

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CA-170 is the first small-molecule inhibitor targeted at PD-L1 that was introduced to phase I and II clinical trials. We, however, unambiguously determined that there is in fact no direct binding between CA-170 and its peptidic precursor AUNP-12 to PD-L1. In the NMR binding assay, neither of these molecules showed any interactions with the one- or two-domain PD-L1 in the human and mice variants as well as human PD-1. CA-170 and AUNP-12 were also not able to dissociate complex formation in the isolated system of the HTRF assay and cell-based assay mimicking in vivo conditions. All measurements were cross-validated with positive controls: peptide-57 and small-molecule BMS-1166. Therefore, proposed mechanism of the direct blocking of hPD-1/hPD-L1 interactions with CA-170 has to be changed.[Molecules. 2019 Aug 1;24(15):2804.]

C13H22N6O7

374.3498

374.154

C, 41.71; H, 5.92; N, 22.45; O, 29.92

1673560-66-1

PD-1-IN-17 TFA

131998882

White to off-white solid powder

-6.7

227

7

10

10

26

507

4

O1C(C([H])(C([H])(C([H])([H])[H])O[H])N([H])[H])=NN=C1C([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])C(N([H])C([H])(C(=O)O[H])C([H])([H])O[H])=O

SRNQPYBWRIETFQ-XKBZYTNZSA-N

InChI=1S/C13H22N6O7/c1-5(21)9(15)11-19-18-10(26-11)6(2-3-8(14)22)16-13(25)17-7(4-20)12(23)24/h5-7,9,20-21H,2-4,15H2,1H3,(H2,14,22)(H,23,24)(H2,16,17,25)/t5-,6+,7+,9+/m1/s1

(2S)-2-[[(1S)-4-amino-1-[5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,3,4-oxadiazol-2-yl]-4-oxobutyl]carbamoylamino]-3-hydroxypropanoic acid

PD-1-IN-17; PD-1-IN-17 free base; PD1-IN-1; (2S)-2-[[(1S)-4-amino-1-[5-[(1S,2R)-1-amino-2-hydroxypropyl]-1,3,4-oxadiazol-2-yl]-4-oxobutyl]carbamoylamino]-3-hydroxypropanoic acid; (S)-2-(3-((S)-4-Amino-1-(5-((1S,2R)-1-amino-2-hydroxypropyl)-1,3,4-oxadiazol-2-yl)-4-oxobutyl)ureido)-3-hydroxypropanoic acid; CHEMBL4458504; SCHEMBL19450456;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~333.91 mM)
H2O : ≥ 100 mg/mL (~267.13 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.56 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (5.56 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (5.56 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。