BEZ235 (NVP-BEZ235)
(Synonyms: Dactolisib) 目录号 : GC10060
NVP-BEZ235 是一种新型治疗剂，靶向 PI3K/Akt/mTOR（磷脂酰肌醇 3-激酶）通路中的 2 个分子，即 PI3K 和 mTOR。
Cas No.:915019-65-7
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 |
Glioma stem cells |
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Preparation Method |
NVP-BEZ235 was dissolved in DMSO to obtain a stock concentration of 10 mmol/L, which was aliquoted and stored at -20 °C and diluted to the desired final concentration in DMEM/F12 at the time of use. The GSC cells were treated with various concentrations of NVP-BEZ235 for 24, 48, or 72 h. |
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Reaction Conditions |
10,20,40,80,160,320µM for 24, 48, or 72 h |
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Applications |
NVP-BEZ235 treatment significantly increased radiation sensitivity in GSCs, and the inhibition of autophagy by 3-MA blocked NVP-BEZ235-mediated radiosensitization. |
| Animal experiment [2]: | |
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Animal models |
male transgenic Tg (Thy1-APPSweLon) 41Ema (T41) mice and their wild-type (WT) littermates. |
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Preparation Method |
Animals were treated by oral gavage with 5 or 25 mg/kg of NVP-BEZ235, diluted in 1-metyl 2-pirrolidone 10% in PEG 300, or vehicle, once a day for 14 days. According to the genotype (WT or T41) and the treatment (NVP-BEZ235 or vehicle), the animals were divided into five groups: WT + Vehicle, WT + NVP-BEZ235 25 mg/kg (WT + BEZ 25), T41 + Vehicle, T41 + NVP-BEZ235 5 mg/kg (T41 + BEZ 5), and T41 + NVP-BEZ235 25 mg/kg (T41 + BEZ 25). |
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Dosage form |
5 or 25 mg/kg, oral |
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Applications |
BEZ 5 mg/kg significantly reversed this memory impairment in T41 mice. Memory loss is the main sign of Alzheimer's disease (AD) |
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References: [1]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690. |
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NVP-BEZ235 is a novel therapeutic agent that targets 2 molecules in thePI3K/Akt/mTOR (phosphatidylinositol 3-kinase) pathway, PI3K and mTOR. It is an ATP-competitive pan-class I PI3K inhibitor that is effective against p110α with hotspot mutations, and likewise inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2 [1]. NVP-BEZ235 antagonizes the PI3K/mTOR signaling pathway and induces cell-cycle arrest, autophagy, and downregulation of vascular endothelial growth factor in glioma cells. NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated (ATM) and DNA-PK catalytic subunits (DNA-PKcs), arrests cell cycle, and induces apoptosis [2].
NVP-BEZ235 treated colorectal cancer (CRC) cell lines resulted in transient PI3K blockade, sustained decreases in mTORC1/mTORC2 signaling, and a corresponding decrease in cell viability (IC50 = 9.0-14.3 nM) [3]. All cell lines with PI3K-activating mutations or Pten deletions (A2780, IGROV1, MOVCAR18, OAW42, and SKOV3) were highly sensitive to NVP-BEZ235 (IC50 range 26-70 nM). In contrast, HEYC2, OV167, OV207, and OVCAR5 cells, that lack PI3K-activating mutations or Pten deletions, had an IC50 ≥ 100 nM (IC50 range 100-210 nM) for NVP-BEZ235. Overall, a statistically significant difference between the average NVP-BEZ235 IC50 for cell lines with PI3K mutations or Pten deletions (IC50 = 48.5 ± 8.1 nM) compared to cell lines that lack these mutations (IC50 = 95.9 ± 18.4 nM) [1].
Mouse model of Alzheimer's disease (AD) that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of NVP-BEZ235. Ten-months-old T41 animals were treated for 14 days with NVP-BEZ235 or vehicle via oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ1-42 content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with NVP-BEZ235 (5 mg/kg) reduced social memory impairment in T41 mice. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. NVP-BEZ235 diminished IL-10 levels in T41 mice [4].
References:
[1]. C. Santiskulvong, G.E. Konecny, M. Fekete, et al. Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma. Clin. Cancer Res., 17 (2011), pp. 2373-2384
[2]: Wang WJ, Long LM, Yang N, et al. NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro. Acta Pharmacol Sin. 2013;34:681-690.
[3]. J. Roper, M.P. Richardson, W.V. Wang, L.G. Richard, W. Chen, E.M. Coffee, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS ONE, 6 (2011), p. e25132
[4]. P.M.Q. Bellozi, G.F. Gomes, L.R. de Oliveira, et al. NVP-BEZ235 (Dactolisib) has protective effects in a transgenic mouse model of Alzheimer's disease. Frontiers in Pharmacology, 10 (2019), p. 1345
NVP-BEZ235 是一种新型治疗剂,靶向 PI3K/Akt/mTOR（磷脂酰肌醇 3-激酶）通路中的 2 个分子,即 PI3K 和 mTOR。它是一种 ATP 竞争性泛 I 类 PI3K 抑制剂,对具有热点突变的 p110α 有效,同样抑制哺乳动物雷帕霉素靶标复合物 1 (mTORC1) 和 mTORC2 [1]。 NVP-BEZ235 拮抗 PI3K/mTOR 信号通路并诱导细胞周期停滞、自噬和神经胶质瘤细胞中血管内皮生长因子的下调。 NVP-BEZ235 也是一种有效的放射增敏剂,可抑制共济失调性毛细血管扩张症突变 (ATM) 和 DNA-PK 催化亚基 (DNA-PKcs)、阻滞细胞周期并诱导细胞凋亡[2]。
NVP-BEZ235 处理的结直肠癌 (CRC) 细胞系导致短暂的 PI3K 阻断、mTORC1/mTORC2 信号持续降低以及细胞活力相应降低（IC50 = 9.0-14.3 nM ) [3]。所有具有 PI3K 激活突变或 Pten 缺失的细胞系（A2780、IGROV1、MOVCAR18、OAW42 和 SKOV3）对 NVP-BEZ235 高度敏感（IC50 范围 26-70 nM）。相反,缺乏 PI3K 激活突变或 Pten 缺失的 HEYC2、OV167、OV207 和 OVCAR5 细胞的 IC50 ≥ 100 nM（IC50 范围为 100- 210 nM）对于 NVP-BEZ235。总体而言,与细胞系相比,具有 PI3K 突变或 Pten 缺失的细胞系的平均 NVP-BEZ235 IC50（IC50 = 48.5 ± 8.1 nM）之间存在统计学显着差异缺乏这些突变 (IC50 = 95.9 ± 18.4 nM) [1]。
阿尔茨海默病 (AD) 小鼠模型表达了一种突变型淀粉样蛋白-β 前体蛋白（T41 小鼠）,以研究 NVP-BEZ235 的作用。 10 个月大的 T41 动物通过口服强饲法用 NVP-BEZ235 或载体治疗 14 天,然后进行社交记忆、开放场和情境条件恐惧测试。制备海马切片并评估Aβ1-42含量、NeuN、Iba-1、CD68和GFAP。进一步处理组织以通过细胞计数珠阵列评估细胞因子水平。用 NVP-BEZ235 (5 mg/kg) 治疗可减少 T41 小鼠的社交记忆障碍。该药降低了海马CA3区的CD68/Iba-1比值。 NVP-BEZ235 降低了 T41 小鼠的 IL-10 水平[4]。
| Cas No. | 915019-65-7 | SDF | |
| 别名 | Dactolisib | ||
| 化学名 | 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile | ||
| Canonical SMILES | CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3N(C2=O)C)C5=CC6=CC=CC=C6N=C5 | ||
| 分子式 | C30H23N5O | 分子量 | 469.55 |
| 溶解度 | ≥ 7.8mg/mL in DMSO | 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 | 2.1297 mL | 10.6485 mL | 21.297 mL |
| 5 mM | 0.4259 mL | 2.1297 mL | 4.2594 mL |
| 10 mM | 0.213 mL | 1.0648 mL | 2.1297 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。
NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation
Int J Biol Sci2020 Jan 14;16(4):682-693.PMID: 32025215DOI: 10.7150/ijbs.37592
NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor, currently in phase 1/2 clinical trials, exhibiting clinical efficiency in treatment of numerous malignancies including thyroid cancer. Cancer cells harboring mutant p53 was widely reported to be blunt to pharmaceutical therapies. However, whether this genotype dependent effect also presents in thyroid cancer when treated with NVP-BEZ235 remains unknown. Therefore, in this study, the tumor suppressing effects of NVP-BEZ235 in thyroid cancer cell lines and in-vivo xenograft mouse model harboring different p53 status were examined. The antitumor effects were confirmed in p53 mutant thyroid cancer cells, though less prominent than p53 wild type cells. And for the p53 mutant cells, p53-independent upregulation of p21 plays a critical role in their response to NVP-BEZ235. Moreover, GSK3¦¯¦catenin signaling inhibition was implicated in the p21-mediated G0/G1 cell cycle arrest in both p53 wild type and mutant thyroid cancer cells treated with NVP-BEZ235.
Studies of NVP-BEZ235 in melanoma
Curr Cancer Drug Targets2013 Feb;13(2):165-74.PMID: 23215722DOI: 10.2174/1568009611313020006
The PI3k pathway represents an attractive target for drug development in melanoma, as numerous studies have shown that this pathway is active in malignant melanocytes. In addition, previous work has shown that multi-level targeting of this pathway might be more effective than targeting the pathway at a single level. In this review, we discuss targeting different members of this pathway, potential escape mechanisms, classes of specific molecular inhibitors, and development of NVP-BEZ235, a novel dual PI3k/mTOR inhibitor.
NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells
Cancer Treat Res Commun2021;27:100340.PMID: 33636591DOI: 10.1016/j.ctarc.2021.100340
Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway activity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway inhibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and basal-like breast cancer (BBC) cell lines. We examined growth, gene expression, and apoptosis in cells treated with NVP-BEZ235 and/or JAKi. Growth and recovery assays showed no significant impact of dual treatment with NVP-BEZ235/JAKi compared to NVP-BEZ235 treatment alone. Gene expression and flow cytometry revealed that single and dual treatments induced apoptosis. Stem gene expression was retained in dual NVP-BEZ235/JAKi treatment samples. Future in vivo studies may give further insight into the impact of combined NVP-BEZ235/JAKi treatment in GBM and BBC.
NVP-BEZ235-induced autophagy as a potential therapeutic approach for multiple myeloma
Am J Transl Res2019 Jan 15;11(1):87-105.PMID: 30787971DOI: 10.1016/j.ejps.2019.04.011
Background: The PI3K/Akt/mTOR pathway is constitutively activated in human multiple myeloma (MM) cell lines and in freshly isolated plasmocytes from patients with MM. The mTOR signaling pathway has been designated an attractive anti-tumor target in multiple myeloma. NVP-BEZ235, a novel, dual class I PI3K/mTOR inhibitor, is an imidazoquinoline derivative. NVP-BEZ235 binds to the ATP-binding clefts of PI3K and mTOR kinase, thereby inhibiting their activities. Increasing evidence shows that NVP-BEZ235 is able to effectively and specifically reverse the hyperactivation of the PI3K/mTOR pathway, resulting not only in potent antiproliferative and antitumor activities in a broad range of cancer cell lines and experimental tumors but also in autophagy.
Method: The antitumor, apoptosis, and autophagy effects of NVP-BEZ235 were measured in three MM cell lines, two leukemia cell lines, and primary CD138+ myeloma cells from MM patients and nude mouse MM models. In addition, the relationships between autophagy, cell death and apoptosis induced by NVP-BEZ235 were analyzed in MM cells. Furthermore, we explored the mechanism of autophagy induced by NVP-BEZ235 in MM cells.
Results: NVP-BEZ235 inhibited proliferation and induced apoptosis and autophagy in MM cells and in primary MM cells from patients and nude mouse MM models. Autophagy played an important role in the cell death and apoptosis of MM cell lines induced by NVP-BEZ235, and the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway.
Conclusions: In this study, NVP-BEZ235 showed the strongest antitumor and autophagy induction activity. Moreover, the mechanism involved the mTOR2-Akt-FOXO3a-BNIP3 pathway. Our study lays a theoretical foundation for NVP-BEZ235 clinical application.