CSN5i-3
目录号 : GC34340
CSN5i-3是一种新型、强效、高选择性且具有口服生物利用度的小分子抑制剂，其作用靶点为CSN5/Jab1（COPS5）蛋白——该蛋白是COP9信号体复合物的关键蛋白水解亚基。CSN5i-3对此靶点的抑制活性极高，IC50值为5.8nM。
Cas No.:2375740-98-8
Sample solution is provided at 25 µL, 10mM.
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CSN5i-3 is a novel, potent, highly selective, and orally bioavailable small molecule inhibitor that targets the CSN5/Jab1 (COPS5) protein—a key protein hydrolytic subunit of the COP9 signaling complex. CSN5i-3 exhibits extremely high inhibitory activity against this target, with an IC50 value of 5.8nM[1, 2]. The core function of CSN5 is to cleave the NEDD8 modification from the Cullin-RING E3 ubiquitin ligase. CSN5i-3 can potently inhibit this de-Neddase activity of CSN5, thereby interfering with the normal function of the CRL ubiquitin ligase[3].
In vitro, treatment of human breast cancer BT474 and SKBR3 cells with CSN5i-3 (2µM) for 24h significantly induced apoptosis and G1 phase cell cycle arrest, and increased the levels of the apoptosis marker cleaved PARP and the cell cycle-related protein p27[4]. Treatment of human umbilical vein endothelial cells (HUVECs) with CSN5i-3 (1, 4µM) for 5h induced a significant weakening of endothelial barrier function, induced the expression of RhoGTPase RhoB in endothelial cells, and formed actin stress fibers[5].
In vivo, subcutaneous injection of CSN5i-3 (10mg/kg) into MDA-MB-231 cell xenograft mice for 18 days inhibited tumor growth in mice, and combined treatment with Talazoparib significantly enhanced the antitumor efficacy[6].
References:
[1] Schlierf A, Altmann E, Quancard J, et al. Targeted inhibition of the COP9 signalosome for treatment of cancer[J]. Nature communications, 2016, 7(1): 13166.
[2] Yin L, Xue Y, Shang Q, et al. Pharmaceutical inhibition of neddylation as promising treatments for various cancers[J]. Current Topics in Medicinal Chemistry, 2019, 19(12): 1059-1069.
[3] Wu J T, Chan Y R, Chien C T. Protection of cullin–RING E3 ligases by CSN–UBP12[J]. Trends in cell biology, 2006, 16(7): 362-369.
[4] Xiao H, Claret F X, Shen Q. The novel Jab1 inhibitor CSN5i-3 suppresses cell proliferation and induces apoptosis in human breast cancer cells[J]. Neoplasma, 2019, 66(3).
[5] Majolée J, Pronk M C A, Jim K K, et al. CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity[J]. Scientific reports, 2019, 9(1): 8131.
[6] Peng X, Wang Y, Yu Z, et al. Jab1 regulates HRR mRNA stability to modulate PARP inhibitor sensitivity in triple-negative breast cancer[J]. Molecular Cancer, 2025, 24(1): 217.
CSN5i-3是一种新型、强效、高选择性且具有口服生物利用度的小分子抑制剂，其作用靶点为CSN5/Jab1（COPS5）蛋白——该蛋白是COP9信号体复合物的关键蛋白水解亚基。CSN5i-3对此靶点的抑制活性极高，IC50值为5.8nM[1, 2]。CSN5的核心功能是从Cullin-RING E3泛素连接酶上切除NEDD8修饰，CSN5i-3能够通过强效抑制CSN5的这一去Nedd化酶活过程，从而干扰CRL泛素连接酶的正常功能[3]。
在体外，CSN5i-3（2µM）处理人乳腺癌BT474和SKBR3细胞24h，均显著诱导了细胞凋亡和G1期细胞周期阻滞，提高了凋亡标志物cleaved PARP和细胞周期相关蛋白p27的水平[4]。CSN5i-3（1, 4µM）处理人脐静脉内皮细胞（HUVECs）5h，诱导了内皮屏障功能的显著减弱，诱导了内皮细胞中RhoGTP 酶RhoB的表达，并形成肌动蛋白应力纤维[5]。
在体内，CSN5i-3（10mg/kg）通过皮下注射治疗MDA-MB-231细胞异种移植小鼠18天，抑制了小鼠体内肿瘤生长，与Talazoparib联合治疗显著增强了抗肿瘤疗效[6]。
| Cell experiment [1]: | |
Cell lines | BT474、SKBR3 cells |
Preparation Method | BT474 and SKBR3 cells were seeded in a 6-well plate. After exposure to 2µM CSN5i-3 for 24h, cells were stained with Annexin V-FlTC and analyzed by FACSCalibur to assess the apoptotic cell percentages. |
Reaction Conditions | 2µM; 24h |
Applications | Jab1 inhibitor CSN5i-3 can significantly induce apoptosis in BT474 and SKBR3 cells. |
| Animal experiment [2]: | |
Animal models | BALB/c nude mice |
Preparation Method | MDA-MB-231 cells were subcutaneously injected into the right flanks of 4- to 5‐week‐old female BALB/c nude mice. When tumors reached 1000mm3, they were excised, diced into 2mm×2mm×2mm pieces, and implanted into the right flanks of BALB/c nude mice. Tumors were allowed to grow to 100mm3 before random assignment into four groups (n=5): vehicle, CSN5i-3 (10mg/kg), Talazoparib (0.33mg/kg), or a combination of CSN5i-3 and Talazoparib. Tumor size was measured every 3 days. On day 19, mice were euthanized, and tumors were harvested. Tumors were either formalin-fixed or paraffin-embedded for histological analysis. |
Dosage form | 10mg/kg; 18 days; s.c. |
Applications | Combined treatment with CSN5i-3 and Talazoparib significantly enhanced antitumor efficacy. |
References: | |
| Cas No. | 2375740-98-8 | SDF | |
| Canonical SMILES | O=C(C1=CC(C(F)F)=NN1C(C)C)NC2=CC(C3=CC=CC=C3)=C([C@@H]4N5C(CCC[C@@H]4O)=CN=C5)C=C2 | ||
| 分子式 | C28H29F2N5O2 | 分子量 | 505.56 |
| 溶解度 | DMSO: ≥ 100 mg/mL (197.80 mM) | 储存条件 | Store at -20°C, protect from light, stored under nitrogen |
| 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 | 1.978 mL | 9.89 mL | 19.78 mL |
| 5 mM | 395.6 μL | 1.978 mL | 3.956 mL |
| 10 mM | 197.8 μL | 989 μL | 1.978 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。
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet