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
A RAD51 inhibitor
Cas No.:415713-60-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
HeLa, MCF-7，U2OS cells |
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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. |
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Reaction Conditions |
24h，15 μM, 25 μM |
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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]: | |
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Animal models |
Female BALB/c nude mice (6 weeks) |
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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. |
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Dosage form |
50 mg/kg，every 3 days for 30 days |
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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. |
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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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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]
| 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells
Nucleic Acids Res2012 Aug;40(15):7347-57.PMID: 22573178DOI: 10.1093/nar/gks353
Homologous recombination serves multiple roles in DNA repair that are essential for maintaining genomic stability. We here describe RI-1, a small molecule that inhibits the central recombination protein RAD51. RI-1 specifically reduces gene conversion in human cells while stimulating single strand annealing. RI-1 binds covalently to the surface of RAD51 protein at cysteine 319 that likely destabilizes an interface used by RAD51 monomers to oligomerize into filaments on DNA. Correspondingly, the molecule inhibits the formation of subnuclear RAD51 foci in cells following DNA damage, while leaving replication protein A focus formation unaffected. Finally, it potentiates the lethal effects of a DNA cross-linking drug in human cells. Given that this inhibitory activity is seen in multiple human tumor cell lines, RI-1 holds promise as an oncologic drug. Furthermore, RI-1 represents a unique tool to dissect the network of reaction pathways that contribute to DNA repair in cells.