(±)-Nutlin-3
(Synonyms: REL-4-[[(4R,5S)-4,5-双(4-氯苯基)-4,5-二氢-2-[4-甲氧基-2-(1-甲基乙氧基)苯基]-1H-咪唑-1-基]羰基]-2-哌嗪酮) 目录号 : GC14154
(±)-Nutlin-3是一种强效且选择性的MDM2拮抗剂，其IC50为0.09μM。
Cas No.:548472-68-0
Sample solution is provided at 25 µL, 10mM.
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(±)-Nutlin-3 is a potent and selective MDM2 antagonist with IC50 value of 0.09μM[1]. Mouse double minute 2 homolog (MDM2) is an important negative regulator of the tumor suppressor p53, and disrupting the p53-MDM2 interaction activates p53 to inhibit tumor growth[2]. (±)-Nutlin-3 is usually used in the study of tumorigenesis mechanisms and p53 function[3].
In vitro, (±)-Nutlin-3 (10μM; 24h) reduced clonogenic survival of 22RV1 prostate cancer cells, stabilized p53 and p21 proteins, induced G1 arrest and slightly increased apoptosis[4]. (±)-Nutlin-3 (10μM; 48h) markedly induced apoptosis in 29/30 primary B-CLL samples (Annexin-V positivity, loss of ΔΨm, Caspase-3 activation and PARP cleavage), while up-regulating p53, p21, TRAIL-R2 and PIG3 expression, and showed minimal toxicity toward normal CD19⁺ B cells and CD34⁺ hematopoietic progenitors[5].
In vivo, (±)-Nutlin-3 (150mg/kg; p.o.; twice daily for 21 days) combined with Inauhzin (15mg/kg; i.p.; once daily for 21 days) significantly reduced HCT116p53⁺/⁺ xenograft tumor volume in nude mice by 60%, elevated intratumoral p53 and PUMA protein levels, increased TUNEL-positive apoptotic cells and decreased BrdU-labeled proliferating cells[6]. (±)-Nutlin-3 (200mg/kg; p.o.; twice daily for 3 weeks) markedly suppressed primary tumor growth in UKF-NB-3rDOX20 (WT p53) multidrug-resistant neuroblastoma xenografts in nude mice, decreased hepatic and pulmonary MYCN DNA and mRNA levels, reduced metastatic foci and enhanced intratumoral Caspase-3 activity, whereas no effect was observed in p53-mutant UKF-NB-3rVCR10 xenografts[7].
References:
[1] Yu Z, Zhuang C, Wu Y, et al. Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors. Int J Mol Sci. 2014;15(9):15741-15753.
[2] Shinohara T, Uesugi M. In-vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Tanpakushitsu Kakusan Koso. 2007;52(13 Suppl):1816-1817.
[3] Secchiero P, Bosco R, Celeghini C, Zauli G. Recent advances in the therapeutic perspectives of Nutlin-3. Curr Pharm Des. 2011;17(6):569-577.
[4] Supiot S, Hill RP, Bristow RG. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. Mol Cancer Ther. 2008;7(4):993-999.
[5] Secchiero P, Barbarotto E, Tiribelli M, et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006;107(10):4122-4129.
[6] Zhang Y, Zhang Q, Zeng SX, Zhang Y, Mayo LD, Lu H. Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth. Cancer Biol Ther. 2012;13(10):915-924.
[7] Van Maerken T, Ferdinande L, Taildeman J, et al. Antitumor activity of the selective MDM2 antagonist nutlin-3 against chemoresistant neuroblastoma with wild-type p53. J Natl Cancer Inst. 2009;101(22):1562-1574.
(±)-Nutlin-3是一种强效且选择性的MDM2拮抗剂，其IC50为0.09μM[1]。鼠双微体 2（MDM2）是抑癌蛋白p53的重要负调控因子，阻断p53-MDM2相互作用可激活p53，从而抑制肿瘤生长[2]。(±)-Nutlin-3常用于肿瘤发生机制及p53功能研究[3]。
在体外，(±)-Nutlin-3（10μM；24h）可降低22RV1前列腺癌细胞的克隆存活率，稳定p53和p21蛋白，诱导G1期阻滞并轻度增加细胞凋亡[4]。(±)-Nutlin-3（10μM；48h）可显著诱导29/30例原发性B-CLL样本发生凋亡（表现为Annexin-V 阳性、线粒体膜电位丧失、Caspase-3激活及PARP裂解），上调p53、p21、TRAIL-R2及PIG3表达，而对正常CD19⁺B细胞及CD34⁺造血祖细胞毒性极低[5]。
在体内，(±)-Nutlin-3（150mg/kg；口服；每日2次，连续 21天）联合Inauhzin（15mg/kg；腹腔注射；每日1次，连续21天）使裸鼠HCT116-p53⁺/⁺异种移植瘤体积显著缩小60%，提升肿瘤内p53与PUMA蛋白水平，增加TUNEL 阳性凋亡细胞并减少BrdU标记的增殖细胞比例[6]。(±)-Nutlin-3（200mg/kg；口服；每日2次，连续3周）显著抑制裸鼠UKF-NB-3rDOX20（WT p53）耐药神经母细胞瘤异种移植瘤的原发肿瘤生长，降低肝脏和肺脏的MYCN DNA和mRNA水平，减少转移灶数目并增强肿瘤内Caspase-3活性；而在p53突变的 UKF-NB-3rVCR10异种移植瘤中未见上述效应[7]。
| Cell experiment [1]: | |
Cell lines | Human malignant prostate cancer 22RV1 cells |
Preparation Method | Human malignant prostate cancer 22RV1 cells were grown in RPMI 1640 supplemented with 10% FCS and 1% L-glutamine. Cells were counted and plated at different densities 15h before (±)-Nutlin-3 exposure. Then cells were treated with 10μM (±)-Nutlin-3 for 24h. Cells were irradiated at room temperature using a 137Cs g-ray irradiator at a dose rate of 0.9 Gy/min. Following incubation, drug was removed and fresh medium was added. Colonies were stained and counted under a microscope, with 50 cells as the minimum number to define a surviving colony. The best-fit survival curve was generated according to a linear-quadratic survival model and the mean inactivation dose (area under survival curve) was calculated. |
Reaction Conditions | 10μM; 24h |
Applications | (±)-Nutlin-3 reduced clonogenic survival of 22RV1 prostate cancer cells. |
| Animal experiment [2]: | |
Animal models | female SCID mice |
Preparation Method | Five-week-old female SCID mice were subcutaneously inoculated with 3×106 HCT116p53+/+ cells in the right flank and tumor growth was monitored with calipers. After the mean tumor volume reached 50–100mm3, animals were administered Inauhzin (15mg/kg; i.p.; once daily for 21 days), (±)-Nutlin-3 (150mg/kg; p.o.; twice daily for 21 days), or vehicles (4% DMSO for Inauhzin, EtOH:Tween:5% glucose = 5:5:90 for (±)-Nutlin-3). Tumor volume was measured every other day, and inhibition of tumor growth (T/C) was calculated on the last day of treatment. To determine p53 induction in vivo, tumors were harvested and homogenized in RIPA buffer with a protease inhibitor mixture. Tumor homogenates were analyzed by western blot. |
Dosage form | 150mg/kg; p.o.; twice daily for 21 days |
Applications | (±)-Nutlin-3 combined with Inauhzin significantly reduced HCT116p53⁺/⁺ xenograft tumor volume in nude mice by 60%, elevated intratumoral p53. |
References: | |
| Cas No. | 548472-68-0 | SDF | |
| 别名 | REL-4-[[(4R,5S)-4,5-双(4-氯苯基)-4,5-二氢-2-[4-甲氧基-2-(1-甲基乙氧基)苯基]-1H-咪唑-1-基]羰基]-2-哌嗪酮 | ||
| 化学名 | 4-(4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-2-one | ||
| Canonical SMILES | ClC1=CC=C(C=C1)C2N(C(N(C3)CCNC3=O)=O)C(C(C=CC(OC)=C4)=C4OC(C)C)=NC2C(C=C5)=CC=C5Cl | ||
| 分子式 | C30H30Cl2N4O4 | 分子量 | 581.49 |
| 溶解度 | DMSO : ≥ 50 mg/mL (85.99 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 | 1.7197 mL | 8.5986 mL | 17.1972 mL |
| 5 mM | 0.3439 mL | 1.7197 mL | 3.4394 mL |
| 10 mM | 0.172 mL | 0.8599 mL | 1.7197 mL |
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| 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 |
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| % 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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