AZD4635
(Synonyms: HTL1071; AZD4635) 目录号 : GC19049
AZD4635是一种强效、选择性的口服腺苷2A受体（A2AR）抑制剂，Ki值为1.7nM。
Cas No.:1321514-06-0
Sample solution is provided at 25 µL, 10mM.
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AZD4635 is a potent, selective, and oral adenosine 2A receptor (A2AR) inhibitor, with a Ki value of 1.7nM [1]. AZD4635 can increase the expression of CD25 (IL2Ra), an activation marker on CD8 T cells, and increase the expression of granzyme B on CD4 and CD8 T cells to improve immune activation[2]. AZD4635 has been widely used in different animal models to reduce tumor burden and enhance antitumor immunity [3].
In vitro, AZD4635 treatment at 3µM for 30min significantly reversed the immunosuppressive effect of 5µM 5 '-(N-ethylcarboxamide) adenosine (NECA) on dendritic cells, and increased the expression of ovalbumin (OVA)[4]. After stimulation with anti-CD3 and anti-28 monoclonal antibodies, combined treatment with anti-PD-L1 antibody (10µg/ml) and AZD4635 (0.2 µM) for 6 hours enhanced CD8+ T cell function and increased IL-2 and IFN-γ secretion[5].
In vivo, AZD4635 (25mg/kg) administered by gavage once daily for 15 days in combination with sodium polyoxotungstate (POM-1) and anti-CD73 antibody treatment resulted in enhanced T cell activation in the spleen and increased IFN-γ and monocyte levels in the spleen and bone marrow in a mouse model of myeloma[6].
References:
[1] Borodovsky A, Wang Y, Ye M, et al. Preclinical pharmacodynamics and antitumor activity of AZD4635, a novel adenosine 2A receptor inhibitor that reverses adenosine mediated T cell suppression[J]. Cancer Research, 2017, 77(13_Supplement): 5580-5580.
[2] Budhu S, Mane M, Bah M A, et al. Optimizing breast cancer therapy by inhibiting the adenosine receptor and oxygen consumption[J]. Cancer Research, 2023, 83(7_Supplement): 2517-2517.
[3] Borodovsky A, Wang Y, Ye M, et al. Inhibition of A2AR by AZD4635 induces anti-tumor immunity alone and in combination with anti-PD-L1 in preclinical models[J]. Cancer Research, 2018, 78(13_Supplement): 3751-3751.
[4] Borodovsky A, Barbon C M, Wang Y, et al. Small molecule AZD4635 inhibitor of A2AR signaling rescues immune cell function including CD103+ dendritic cells enhancing anti-tumor immunity[J]. Journal for Immunotherapy of Cancer, 2020, 8(2): e000417.
[5] Li J, Huang H H, Tu B, et al. Reversal of the CD8+ T-Cell exhaustion induced by chronic HIV-1 infection through combined blockade of the adenosine and PD-1 pathways[J]. Frontiers in Immunology, 2021, 12: 687296.
[6] Yang R, Elsaadi S, Misund K, et al. Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade[J]. Journal for immunotherapy of cancer, 2020, 8(1): e000610.
AZD4635是一种强效、选择性的口服腺苷2A受体（A2AR）抑制剂，Ki值为1.7nM[1]。AZD4635能增加CD8 T细胞上的激活标志物CD25（IL2Rα）的表达，并提高CD4和CD8 T细胞上颗粒酶B的表达，从而改善免疫激活[2]。AZD4635已被广泛用于不同动物模型，以降低肿瘤负荷并增强抗肿瘤免疫[3]。
在体外，使用3µM的AZD4635处理30分钟，显著逆转了5µM的5'-（N-乙基羧基酰胺）腺苷（NECA）对树突状细胞的免疫抑制作用，并增加了卵清蛋白（OVA）的表达[4]。在抗CD3和抗CD28单克隆抗体刺激下，联合使用抗PD-L1抗体（10µg/ml）和AZD4635（0.2µM）处理6小时，增强了CD8 T细胞功能，并增加了IL-2和IFN-γ的分泌[5]。
在体内，在多发性骨髓瘤小鼠模型中，每日一次灌胃给予AZD4635（25mg/kg），持续15天，并联合sodium polyoxotungstate（POM-1）和抗CD73抗体治疗，增强了脾脏中的T细胞活化，并提高了脾脏和骨髓中IFN-γ和单核细胞的水平[6]。
| Cell experiment [1]: | |
Cell lines | Mouse bone marrow-derived progenitor cells |
Preparation Method | Mouse bone marrow-derived precursor cells were cultured for 16 days in complete T cell medium supplemented with 200ng/ml rmFLT3L and 5ng/ml rmGM-CSF. After initial incubation with growth cytokines for 10 days, 3µM AZD4635 or DMSO (as a control) was added, and after 30 minutes of incubation, 5µM NECA was added. After that, the culture with growth cytokines was continued for 6 days before the cells were harvested for analysis. |
Reaction Conditions | 3µM; 30min |
Applications | AZD4635 treatment rescued the immunosuppressive effects of mouse bone marrow-derived progenitor cells and promoted the generation of bone marrow-derived precursors into CD103+ dendritic cell. |
| Animal experiment [2]: | |
Animal models | C57BL/KalwRij mice |
Preparation Method | C57BL/KalwRij mice were raised in a standard sterile environment and injected intravenously with 2×105 5T33 multiple myeloma (MM) cells on day 0 and intraperitoneally with 10mg/kg monoclonal anti-CD73 antibody on days 2, 4, 8, 11, and 15. AZD4635 (25mg/kg) was administered by gavage once a day from day 0, and mice were sacrificed on day 15, and spleen tissues were collected for analysis. |
Dosage form | 25mg/kg/day for 15 days; p.o. |
Applications | AZD4635 treatment resulted in a significant decrease in the number of CD138 MM cells in the spleen of mice, an increase in the number of monocytes, and enhanced T cell activation. |
References: | |
| Cas No. | 1321514-06-0 | SDF | |
| 别名 | HTL1071; AZD4635 | ||
| Canonical SMILES | NC1=NC(C2=CC=C(F)C=C2)=C(C3=CC(Cl)=NC(C)=C3)N=N1 | ||
| 分子式 | C15H11ClFN5 | 分子量 | 315.73 |
| 溶解度 | DMSO : ≥ 83.3 mg/mL (263.83 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 3.1673 mL | 15.8363 mL | 31.6726 mL |
| 5 mM | 633.5 μL | 3.1673 mL | 6.3345 mL |
| 10 mM | 316.7 μL | 1.5836 mL | 3.1673 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。
Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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