RI-1
(Synonyms: 3-氯-1-(3,4-二氯苯基)-4-(4-吗啉基)-1H-吡咯-2,5-二酮) 目录号 : GC18140
RI-1 是一种 RAD51 抑制剂，IC50 范围为 5 至 30 μM。
Cas No.:415713-60-9
Sample solution is provided at 25 µL, 10mM.
RI-1 is a RAD51 inhibitor, with IC50 ranging from 5 to 30 μM. RI-1 binds covalently to the surface of RAD51 protein at cysteine 319. RI-1 inactivates RAD51 by directly binding to a protein surface that serves as an interface between protein subunits in RAD51 filaments. RI-1 can disrupt homologous recombination in human cells[1].RI-1 sensitizes cells to DNA damage by directly and specifically disrupting HsRAD51.RI-1covalently attaches to HsRAD51 protein, thereby inhibiting the ability of RAD51 to form filaments on ssDNA. RI-1 can inhibit sub-nuclear accumulation of HsRAD51 protein at sites of DNA damage, and this inhibitory activity sensitizes various cancer cell types to cross-linking chemotherapy[1].
In HeLa, MCF-7 and U2OS cells, RI-1 significantly sensitized cells to MMC. The magnitude of sensitization achieved with 25uM RI-1 was 2.5-3fold, depending on the cell type. These data suggest that RI-1 can specifically interfere with RAD51 functions in human cancer cells, thereby rendering them more susceptible to the lethal effects of oncologic treatment[1].In Huh7 and HCCLM3 cells,XRCC2 overexpression accelerates mtDNA level recovery, but treatment with RI-1 can deplete RAD51 and prevent mtDNA level recovery[3]. Rad51 inhibitor RI-1 to inhibit the HR in oocytes. 60 μM RI-1 exposure has no obvious effects on the PBE（polar body extrusion） rates of normal oocytes[4]. Ri-1 reduced γ-H2AX foci in G2 phase cells and resulted in elevated levels of unrepaired DNA double-strand breaks 6 hours after radiation[5].VS tumors expressed RAD51. VS may evade radiation injury by entering cell cycle arrest and upregulating RAD51-dependent repair of radiation-induced double-stranded breaks in DNA. Although there was variability in responses among individual primary VS cells, RAD51 inhibition with RI-1 reduced RAD51-dependent DNA repair to enhance radiation toxicity in VS cells[6]
In an MDA-MB-157 breast cancer model, mice were randomly assigned to one of four groups to receive vehicle, ABT888, RI-1, or combination of ABT888 and RI-1. The combination of ABT888 and RI-1 resulted in significant inhibition of tumor growth.The combination of ABT888 and RI-1 showed a slower growth and a decreased tumor weight of tumors[2]
References:
[1]. Budke B, Logan HL, et,al. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 2012 Aug;40(15):7347-57. doi: 10.1093/nar/gks353. Epub 2012 May 9. PMID: 22573178; PMCID: PMC3424541.
[2]. Shi Y, Jin J, et,al. DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors. Neoplasia. 2019 Jun;21(6):533-544. doi: 10.1016/j.neo.2019.04.001. Epub 2019 Apr 24. PMID: 31029033; PMCID: PMC6484230.
[3]. Zhao Z, He K, et,al. XRCC2 repairs mitochondrial DNA damage and fuels malignant behavior in hepatocellular carcinoma. Cancer Lett. 2021 Aug 1;512:1-14. doi: 10.1016/j.canlet.2021.04.026. Epub 2021 May 5. PMID: 33964350.
[4]. Ma JY, Feng X, et,al. The repair of endo/exogenous DNA double-strand breaks and its effects on meiotic chromosome segregation in oocytes. Hum Mol Genet. 2019 Oct 15;28(20):3422-3430. doi: 10.1093/hmg/ddz156. PMID: 31384951.
[5]. Bee L, Fabris S, et,al. The efficiency of homologous recombination and non-homologous end joining systems in repairing double-strand breaks during cell cycle progression. PLoS One. 2013 Jul 11;8(7):e69061. doi: 10.1371/journal.pone.0069061. PMID: 23874869; PMCID: PMC3708908.
[6]. Thielhelm TP, Nourbakhsh A, et,al. RAD51 Inhibitor and Radiation Toxicity in Vestibular Schwannoma. Otolaryngol Head Neck Surg. 2022 Mar 1:1945998221083506. doi: 10.1177/01945998221083506. Epub ahead of print. PMID: 35230908.
RI-1 是一种 RAD51 抑制剂，IC50 范围为 5 至 30 μM。 RI-1 在半胱氨酸 319 处与 RAD51 蛋白表面共价结合。RI-1 通过直接结合作为 RAD51 丝中蛋白质亚基之间界面的蛋白质表面来灭活 RAD51。 RI-1可破坏人体细胞中的同源重组[1]。RI-1通过直接特异性破坏HsRAD51使细胞对DNA损伤敏感。RI-1共价结合HsRAD51蛋白，从而抑制RAD51的能力在 ssDNA 上形成细丝。 RI-1 可抑制 HsRAD51 蛋白在 DNA 损伤位点的亚核积累，这种抑制活性可使多种癌细胞类型对交联化疗敏感[1]。
在 HeLa、MCF-7 和 U2OS 细胞中，RI-1 使细胞对 MMC 显着敏感。取决于细胞类型，用 25uM RI-1 实现的致敏幅度为 2.5-3 倍。这些数据表明，RI-1 可以特异性干扰人类癌细胞中的 RAD51 功能，从而使它们更容易受到肿瘤治疗的致死作用[1]。在 Huh7 和 HCCLM3 细胞中，XRCC2 过表达加速mtDNA 水平恢复，但用 RI-1 处理可以耗尽 RAD51 并阻止 mtDNA 水平恢复[3]。 Rad51 抑制剂 RI-1 可抑制卵母细胞中的 HR。 60 μM RI-1暴露对正常卵母细胞PBE（polar body extrusion）率无明显影响[4]。 Ri-1 减少 G2 期细胞中的 γ-H2AX 灶，导致辐射后 6 小时未修复的 DNA 双链断裂水平升高[5]。VS 肿瘤表达 RAD51。 VS 可以通过进入细胞周期停滞和上调辐射诱导的 DNA 双链断裂的 RAD51 依赖性修复来逃避辐射损伤。尽管单个原代 VS 细胞的反应存在差异，但 RI-1 对 RAD51 的抑制减少了 RAD51 依赖性 DNA 修复，从而增强了 VS 细胞的辐射毒性[6]
在 MDA-MB-157 乳腺癌模型中，小鼠被随机分配到四组中的一组接受载体、ABT888、RI-1 或 ABT888 和 RI-1 的组合。 ABT888和RI-1的组合导致肿瘤生长的显着抑制。ABT888和RI-1的组合显示出肿瘤的生长减慢和肿瘤重量降低[2]
| Cell experiment [1]: | |
|
Cell lines |
HeLa, MCF-7，U2OS cells |
|
Preparation Method |
Human cell lines were sequentially incubated for 24 h in media containing varying concentrations of mitomycin C, followed by 24 h in media containing RI-1. Cells were then allowed to grow in drug-free media for an additional 7–9 days. |
|
Reaction Conditions |
24h，15 μM, 25 μM |
|
Applications |
In all three cell types, RI-1 significantly sensitized cells to MMC. The magnitude of sensitization was calculated as a function of the concentration of MMC required to kill 50% of cells. The magnitude of sensitization achieved with 25 uM RI-1 was 2.5-3 fold, depending on the cell type. These data suggest that RI-1 can specifically interfere with RAD51 functions in human cancer cells, thereby rendering them more susceptible to the lethal effects of oncologic treatment[1]. |
| Animal experiment [2]: | |
|
Animal models |
Female BALB/c nude mice (6 weeks) |
|
Preparation Method |
Mice bearing MDA-MB-157 xenografts with a tumor volume of 100mm3(±50), was then randomly grouped and treated by intraperitoneal injection every 3 days for 30 days with RI-1 (50 mg/kg), ABT888 (25 mg/kg), a combination of RI-1 and ABT888, or no treated. Tumors were taken 8 hours after last drug administration for immunofluorescence assay. |
|
Dosage form |
50 mg/kg，every 3 days for 30 days |
|
Applications |
The combination of ABT888 and RI-1 resulted in significant inhibition of tumor growth.The combination of ABT888 and RI-1 showed a slower growth and a decreased tumor weight of tumors. |
|
References: [1]. Budke B, Logan HL, et,al. RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 2012 Aug;40(15):7347-57. doi: 10.1093/nar/gks353. Epub 2012 May 9. PMID: 22573178; PMCID: PMC3424541. [2]. Shi Y, Jin J, et,al. DAXX, as a Tumor Suppressor, Impacts DNA Damage Repair and Sensitizes BRCA-Proficient TNBC Cells to PARP Inhibitors. Neoplasia. 2019 Jun;21(6):533-544. doi: 10.1016/j.neo.2019.04.001. Epub 2019 Apr 24. PMID: 31029033; PMCID: PMC6484230. |
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| Cas No. | 415713-60-9 | SDF | |
| 别名 | 3-氯-1-(3,4-二氯苯基)-4-(4-吗啉基)-1H-吡咯-2,5-二酮 | ||
| 化学名 | 3-chloro-1-(3,4-dichlorophenyl)-4-morpholin-4-ylpyrrole-2,5-dione | ||
| Canonical SMILES | C1COCCN1C2=C(C(=O)N(C2=O)C3=CC(=C(C=C3)Cl)Cl)Cl | ||
| 分子式 | C14H11Cl3N2O3 | 分子量 | 361.61 |
| 溶解度 | ≥ 18.1 mg/mL in DMSO, ≥ 8.89 mg/mL in EtOH with gentle 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 | 2.7654 mL | 13.8271 mL | 27.6541 mL |
| 5 mM | 0.5531 mL | 2.7654 mL | 5.5308 mL |
| 10 mM | 0.2765 mL | 1.3827 mL | 2.7654 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: >99.50%
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