RAD51 Inhibitor B02
(Synonyms: B02) 目录号 : GC19306
RAD51 Inhibitor B02是一种人RAD51重组酶的特异性抑制剂（IC50值为27.4μM），对大肠杆菌中的同系物RecA没有抑制作用（IC50>250μM）。
Cas No.:1290541-46-6
Sample solution is provided at 25 µL, 10mM.
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RAD51 Inhibitor B02 is a specific inhibitor of the human RAD51 recombinase (with an IC50 value of 27.4μM), and it has no inhibitory effect on the homologous RecA in Escherichia coli (with an IC50 > 250μM) [1]. RAD51 is usually overexpressed in cancer cells. RAD51 Inhibitor B02 can inhibit the binding of RAD51 to single-stranded DNA (ssDNA) and disrupt the binding of double-stranded DNA to RAD51/ssDNA filaments [2-3]. RAD51 Inhibitor B02 can be used to increase the anti-tumor activity of tumor-killing drugs [4].
In vitro, treatment with RAD51 Inhibitor B02 (10μM; 72h) enhanced the sensitivity of the human multiple myeloma cell line NCI-H929 (H929) to doxorubicin (DOX), reducing the IC50 of DOX by 8.4 times [5]. Pre-treatment with RAD51 Inhibitor B02 (5μM; pretreat 1h and 7-10 days) significantly increased the sensitivity of MDA-MB-231 cells to cisplatin while having no significant effect on cell viability, and the IC50 of cisplatin decreased by 4 times when used in combination [6].
In vivo, combined treatment with RAD51 Inhibitor B02 (50mg/kg; once every two days for 4 times; i.p.) and cisplatin significantly inhibited tumor growth in MDA-MB-231 xenograft mice [6]. Treatment with RAD51 Inhibitor B02 (50mg/kg; once every three days for 4 times; i.p.) could slightly reduce tumor growth in A375R xenograft melanoma mice [7].
References:
[1] Huang, F., Motlekar, N.A., Burgwin, C.M., et al. Identification of specific inhibitors of human RAD51recombinase using high-throughput screening. ACS Chem. Biol. 6(6), 628-635 (2011).
[2] King H O, Brend T, Payne H L, et al. RAD51 is a selective DNA repair target to radiosensitize glioma stem cells[J]. Stem cell reports, 2017, 8(1): 125-139.
[3] Huang, F., Mazina, O.M., Zentner, I.J., et al. Inhibition of homologous recombination in human cells by targeting RAD51 recombinase. J. Med. Chem. 55(7), 3011-3020 (2012).
[4] Ward A, Khanna K K, Wiegmans A P. Targeting homologous recombination, new pre-clinical and clinical therapeutic combinations inhibiting RAD51[J]. Cancer treatment reviews, 2015, 41(1): 35-45.
[5] Alagpulinsa D A, Ayyadevara S, Shmookler Reis R J. A small-molecule inhibitor of RAD51 reduces homologous recombination and sensitizes multiple myeloma cells to doxorubicin[J]. Frontiers in oncology, 2014, 4: 289.
[6] Huang F, Mazin A V. A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts[J]. PloS one, 2014, 9(6): e100993.
[7] Makino E, Fröhlich L M, Sinnberg T, et al. Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition[J]. Cell Death & Disease, 2020, 11(7): 581.
RAD51 Inhibitor B02是一种人RAD51重组酶的特异性抑制剂（IC50值为27.4μM），对大肠杆菌中的同系物RecA没有抑制作用（IC50>250μM）[1]。RAD51在癌细胞中通常会过度表达。RAD51 Inhibitor B02可抑制RAD51与单链DNA（ssDNA）的结合，并破坏双链DNA与RAD51/ssDNA细丝的结合 [2-3]。RAD51 Inhibitor B02可用于增加肿瘤杀伤药物的抗肿瘤活性 [4]。
在体外，RAD51 Inhibitor B02（10μM; 72h）处理增强了人多发性骨髓瘤细胞系NCI-H929（H929）对阿霉素（DOX）的敏感性，使DOX的IC50降低了8.4倍 [5]。RAD51 Inhibitor B02（5μM; 预处理1h和7-10 days）处理显著增加了MDA-MB-231细胞对顺铂的敏感性而自身对细胞活力没有显著影响，联合使用下顺铂的IC50降低了4倍 [6]。
在体内，RAD51 Inhibitor B02（50mg/kg; 每两天一次，共4次; i.p.）和顺铂联合治疗显著抑制了MDA-MB-231异种移植小鼠的肿瘤生长 [6]。RAD51 Inhibitor B02（50mg/kg; 每三天一次，共4次; i.p.）治疗可较小程度地减少A375R异种移植黑色素瘤小鼠的肿瘤生长 [7]。
| Cell experiment [1]: | |
Cell lines | MDA-MB-231 cells |
Preparation Method | MDA-MB-231 cells were trypsinized and reseeded in 6-well plates with a density of 500 cells/well. After overnight culture, cells were incubated 1h in complete DMEM media containing B02 (5µM). Cisplatin were diluted in PBS and added to the cells when specified in indicated concentrations. The cells were exposed for 1h, then the cells were washed by PBS three times and refreshed by the media containing B02 (5µM). After 7–10 days, cells were fixed and stained with staining solution (0.05% crystal violet, 50% methanol in PBS); finally cell colonies were counted using an AlphaImager 3400 system with AlphaEaseFC software. |
Reaction Conditions | 5μM; pretreat 1h and 7-10 days |
Applications | The RAD51 Inhibitor B02 pretreatment significantly increased the sensitivity of MDA-MB-231 cells to cisplatin without significantly affecting cell viability. When used in combination, the IC50 of cisplatin decreased by 4 times. |
| Animal experiment [1]: | |
Animal models | NCR nude mice (Orthotopic xenograft model) |
Preparation Method | Log phase MDA-MB-231-Luc cells were collected and washed 3 times with cold PBS. To perform tumor cells inoculation, the female NCR nude mice, anesthetized by inhalation of ∼2% isoflurane, were injected subcutaneously with 0.5×106 cells in 0.1ml through a 27 ½ gauge needle into the fat pad located under the left side of the 4th inguinal mammary gland. After 10 days, when the tumors reached 60–90mm3 the mice (n = 5) were randomly distributed into treatment groups which were treated with RAD51 Inhibitor B02, cisplation, combination of both, RAD51 Inhibitor B02 vehicle, or NS. A control group (n = 5) was left untreated. Cisplatin and B02 were dissolved in NS and cremophor/DMSO/NS (1∶1∶3) vehicle, respectively, immediately before injection. In a combination treatment group, the mice were injected with B02 (50mg/kg or indicated otherwise) and cisplatin (4mg/kg or indicated otherwise). In RAD51 Inhibitor B02 group, mice were injected with RAD51 Inhibitor B02 and NS; in cisplatin group, mice were injected with cisplatin and RAD51 Inhibitor B02 vehicle. Cisplatin (or NS) was administrated 3h after RAD51 Inhibitor B02 (or its vehicle) injection. All the treatments were executed through I.P. injections on day 11, 13, 15 and 17 after tumor cells inoculations. The volume of each individual injection was maintained constant at 100µl. Tumor size measurements performed by a caliper and body weight measurements were carried out every other day. |
Dosage form | 50mg/kg; once every two days, for a total of 4 times; i.p. |
Applications | The combined treatment with RAD51 Inhibitor B02 and cisplatin significantly inhibited the tumor growth in MDA-MB-231 xenograft mice. |
References: | |
| Cas No. | 1290541-46-6 | SDF | |
| 别名 | B02 | ||
| Canonical SMILES | O=C1N(CC2=CC=CC=C2)C(/C=C/C3=CC=CN=C3)=NC4=C1C=CC=C4 | ||
| 分子式 | C22H17N3O | 分子量 | 339.39 |
| 溶解度 | DMSO : ≥ 37 mg/mL (109.02 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.9465 mL | 14.7323 mL | 29.4646 mL |
| 5 mM | 589.3 μL | 2.9465 mL | 5.8929 mL |
| 10 mM | 294.6 μL | 1.4732 mL | 2.9465 mL |
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动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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