BEZ235 (NVP-BEZ235, Dactolisib)

BEZ235 (NVP-BEZ235, Dactolisib)は競争性的なPI3K、mTOR 阻害剤、 p110α, p110γ, p110δ と p110β を作用すると、 IC50 がぞれぞれ 4 nM, 5 nM, 7 nM と 75 nMになる.

目録号S1009
5 5 8レビュー 37製品表彰状
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USD 138 In stock
USD 214 In stock

BEZ235 (NVP-BEZ235, Dactolisib) 化学構造
分子量: 469.55

品質と確認

カスタマーレビュー(8)

Quality Control & MSDS

製品情報

  • Combination Therapy
    併用療法
  • Compare PI3K Inhibitors
    PI3K阻害剤を比較
  • 研究分野

製品の説明

生物活性

情報 BEZ235 (NVP-BEZ235, Dactolisib)は競争性的なPI3K、mTOR 阻害剤、 p110α, p110γ, p110δ と p110β を作用すると、 IC50 がぞれぞれ 4 nM, 5 nM, 7 nM と 75 nMになる.
目標

p110α

p110γ

p110δ

p110β

ATR
IC50

4 nM

5 nM

7 nM

75 nM [1]

21 nM [8]
In vitro試験 BEZ235 significantly reduces the phosphorylation levels of the mTOR activated kinase p70S6K. BEZ235 results in a reduction of S235/S236P-RPS6 levels with IC50 of 6.5 nM. The activity of BEZ23 against mTOR is determined using a biochemical mTOR K-LISA assay with IC50 of 20.7 nM. BEZ235 shows slightly lower activity against its β paralogue with IC50 of 75 nM. The PI3K/Akt/mTOR pathway is often constitutively activated in human tumor cells. BEZ235 blocks PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. Both PTEN-null cell lines PC3M and U87MG show a dose-dependent reduction in cell proliferation when treated with increasing concentrations of BEZ235 with an average GI50 of 10-12 nM. [1] BEZ235 is an mTORC1/2 catalytic inhibitor. [2]
In vivo試験 BEZ235 induces regression of the tumors (69%) without statistically significant effect on body weight gain. Altogether, these preliminary in vivo efficacy results show that BEZ235 causes disease stasis when administered orally as a single agent and can enhance the efficacy of other anticancer agents when used in combination studies. [1]
臨床試験
特集

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ:

[1]

In vitro Protein Kinase, PI3K, and mTOR Assays PI3Kα, β, and δ proteins are composed of the iSH2 domain of p85 NH2-terminally fused to the full-length protein p110 protein, with the exception of α that also does not contain the last 20 amino acids. PI3Kγ is produced as full-length protein deleted for its first 144 amino acids. All constructs are fused to a COOH-terminal His tag for convenient purification and then cloned into the pBlue-Bac4.5 (for α, β, and δ isoforms) or pVL1393 (for γ isoform) plasmids. The different vectors are then cotransfected with BaculoGold WT genomic DNA using methods recommended by the vendor for production of the respective recombinant baculoviruses and proteins. BEZ235 are tested for their activity against PI3K using a Kinase-Glo assay. The kinase reaction is done in 384-well black plate. Each well is loaded with 50 μL of test items (in 90% DMSO) and 5 μL reaction buffer containing 10 μg/mL PI substrate (l-α-phosphatidylinositol; Avanti Polar Lipids; prepared in 3% octyl-glucoside) and the PI3K proteins (10, 25, 10, and 150 nM of p110α, p110β, p110δ, and p110γ, respectively) are then added to it. The reaction is started by the addition of 5 μL of 1 μM ATP prepared in the reaction buffer and is incubated for either 60 (for p110α, p110β, and p110δ) or 120 min (for p110γ). It is terminated by the addition of 10 μL Kinase-Glo buffer. The plates are then read in a Synergy 2 reader for luminescence detection.

細胞アッセイ:

[2]

細胞系 HCT116, DLD-1 and SW480 cells
濃度 0-1 μM
処理時間 48 hours
方法

The human CRC cell lines, HCT116 (PIK3CA mutant; kinase domain at H1047R), DLD-1 (PIK3CA mutant; helical domain at E545K), and SW480 (PIK3CA wild-type) and isogenic DLD-1 PIK3CA mutant as well as wild-type cells are maintained in DMEM with 10% FBS and 1 × Penicillin/Streptomycin. Cells are plated at different initial densities (HCT116: 3 × 103 cells/well, DLD-1: 5.5 × 103 cells/well, SW480: 4.5 × 103 cells/well, DLD-1 PIK3CA mutant: 7 × 103 cells/well, and DLD-1 PIK3CA wild-type: 9 × 103 cells/well) to account for differential growth kinetics. After 16 hours, cells are incubated with increasing concentrations of BEZ235, and the drug-containing growth medium is changed every 24 hours. Cell viability is assessed 16 hours after the initial plating and 48 hours after initiation of drug treatment using the colorimetric MTS assay CellTiter 96® AQueous One Solution Cell Proliferation Assay, as per the manufacturer's instructions. Cell viability after drug treatment is normalized to that of untreated cells also grown for 48 hours. For western blot analysis, cells are plated with zero or maximum inhibitory dose (500 nM) BEZ235 for 2, 6, 24, or 48 hours.

動物実験:

[1]

動物モデル Female Harlan athymic nude mice
製剤 NMP/polyethylene glycol 300 (10/90, v/v)
投薬量 45 mg/kg
管理 p.o.
1

参考

化学情報

Download BEZ235 (NVP-BEZ235, Dactolisib) SDF
分子量 469.55
化学式

C30H23N5O

CAS No. 915019-65-7
別名 N/A
溶解度 (25°C)
  • DMSO 1 mg/mL
  • 水 <1 mg/mL
  • エタノール <1 mg/mL
保管 2年 -20°C
6月-80°Cin DMSO
化学名 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile

研究分野

カスタマーレビュー (8)


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Source Breast Cancer Res , 2011, 13, R52. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Immunofluorescence staining
Cell Lines MCF7 cells, IGF1R cells
Concentrations
Incubation Time
Results We investigated the effect of IGF-1 stimulation on MCF7/IGF-1R 4-OH-TAM resistance in a structurally and physiologically relevant context by use of a modified 3D culture. Both parental MCF7 (Figure a) and MCF7/IGF-1R cells (Figure b) were responsive to E2 or IGF-1 by forming acini on Matrigel, but the response was significantly larger in MCF7/IGF-1R cells with altered a cinar morphogenesis. inhibition of IGF -1R/ERK/Akt signaling by respective kinase inhibitors restored 4-OH-TAM sensitivity of MCF7/IGF-1R cells in 3D culture (Figure c).

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Rating
Source Eur J Cancer, 2010, 46, 1111-1121. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method LanthaScreen assay
Cell Lines JFCR39 cell lines
Concentrations 0.016 μM
Incubation Time
Results As shown in Fig. A, NVP-BEZ235 and other inhibitors all inhibited mTOR in a dose-dependent manner. The IC50 values were calculated and are shown in Fig. B. NVP-BEZ235 inhibited mTOR potently, with IC50 value of 0.002 μM. In contrast, ZSTK474, GDC-0941 and LY294002 weakly inhibited mTOR, with IC50 values of 0.377, 0.413 and 3.86μM, respectively. To further demonstrate their selectivity for class I PI3K, the IC50 values of these inhibitors for mTOR were divided by their corresponding IC50s for class I PI3Ka, and the resulting ratios were plotted in Fig. C. Clearly, ZSTK474 and GDC-0941 revealed much higher selectivity for inhibiting class I PI3K than the other two inhibitors. In contrast, NVP-BEZ235 more potently inhibited the activity of mTOR than that of class I PI3K

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Rating
Source BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Western Blotting
Cell Lines xenografts
Concentrations
Incubation Time
Results Phospholipase A2 group 4A (PLA2G4A) expression was increased after BEZ235 treatment in basal-like xenografts.

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Rating
Source Dr Zhang of Tianjin Medical University. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Western blot
Cell Lines breast cancer cells
Concentrations 0-10 nM
Incubation Time 3 h
Results

Click to enlarge
Rating
Source Dr Zhang of Tianjin Medical University. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Western blot
Cell Lines breast cancer cells
Concentrations 0-50 nM
Incubation Time 3 h
Results

Click to enlarge
Rating
Source Cancer Res, 2010, 70, 4982-4994. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Detection of lipid kinase activities of PI3K p110α mutants
Cell Lines HEK293T cells
Concentrations
Incubation Time
Results "Evaluation of relative kinase activity of these mutants revealed that mutant P449T exhibited gain of function (>2-fold) compared with wild-type PI3K α (Fig. A). With regard to two hotspot mutants (E545K and H1047R), we examined the effect of NVP-BEZ235 and other PI3K inhibitors on their enzymatic activity and found no striking difference in their efficacies compared with wild-type p110α (Fig. B).

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Rating
Source Clin Cancer Res, 2010, 16, 6029-6039. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Synergism studies, Immunoblot assays, Clonogenic assays
Cell Lines Melanoma cell
Concentrations 0.1-100 μM
Incubation Time 1-24 h
Results One of the proposed mechanisms of resistance to PI3KIs is mutation in the Ras-Raf pathway, which are found in more than half of melanomas. By ANOVA, no association was found between the IC50 values of NVP-BEZ235 and the presence or absence of B-Raf mutations (Fig. A). The targets of NVP-BEZ235, pAkt and pP70S6K, were both decreased with exposure to the drug in a time- and dose-dependent fashion, as shown in Figure B for YUVON and YUSIK cell lines. Clonogenicity was studied in YUVON and YUSIK cells with exposure to the dual PI3K/mTOR inhibitor. As shown in Figure C, NVP-BEZ235 effectively inhibits clonogenicity at low nanomolar concentrations.

Click to enlarge
Rating
Source Breast Cancer Res, 2011, 13, R52. BEZ235 (NVP-BEZ235, Dactolisib) purchased from Selleck
Method Western blot, A sulforhodamine B ( SRB) colorimetric assay
Cell Lines MCF7 cells, GF-1R cells
Concentrations 0.01-10 μM
Incubation Time
Results IGF-1-stimulated proliferation was drastically restrained by BEZ235 at either 1 or 10 μM (Figure a).While IGF-1R and ERK signaling remained unaffected in response to IGF-1, the phosphorylation level of Akt was diminished with an increase in the dose of BEZ235, largely at 0.1 μM and entirely at 0.5 μM (Figure b). Likewise, the cell proliferation rate decreased correspondingly to Akt phosphorylation levels, significantly dropping at 0.1μM BEZ235 (Figure c)

製品表彰状 (37)

  • Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. [Wilson TR, et al. Nature 2012;487(7408):505-9]

    PubMed: 22763448
  • An animal model of MYC-driven medulloblastoma. [Pei Y, et al. Cancer Cell 2012;21(2):155-67]

    PubMed: 22340590
  • Metrics other than potency reveal systematic variation in responses to cancer drugs [Fallahi-Sichani M, et al. Nat Chem Biol 2013;9(11):708-14]

    PubMed: 24013279
  • FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. [Elliott NE, et al. Blood 2011;118(14):3911-21]

    PubMed: 21821710
  • Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition. [Shi H, et al. Cancer Res 2011;71(15):5067-74]

    PubMed: 21803746
  • Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. [Yang JY, et al. Cancer Res 2010;70(11):4709-18]

    PubMed: 20484037
  • Correlating phosphatidylinositol 3-Kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. [Dan S, et al. Cancer Res 2010;70(12):4982-94]

    PubMed: 20530683
  • Proteomic characterization of breast cancer xenografts identifies early and late bevacizumab-induced responses and predicts effective drug combinations. [Lindholm EM, et al. Clin Cancer Res 2014;20(2):404-12]

    PubMed: 24192926
  • Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. [Migliardi G, et al. Clin Cancer Res 2012;18(9):2515-25]

    PubMed: 22392911
  • Vertical targeting of the phosphatidylinositol-3 kinase pathway as a strategy for treating melanoma. [Aziz SA, et al. Clin Cancer Res 2010;16(24):6029-39]

    PubMed: 21169255
  • PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. [Beaver JA, et al. Clin Cancer Res 2013;19(19):5413-22]

    PubMed: 23888070
  • MicroSCALE screening reveals genetic modifiers of therapeutic response in melanoma. [Wood KC, et al. Sci Signal 2012;5(224):rs4]

    PubMed: 22589389
  • Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. [Jin C, et al. Oncogene 2013;32(17):2179-88]

    PubMed: 22689062
  • The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. [Todd JR, et al. Oncogene 2012;10.1038/onc.2012.562]

    PubMed: 23246970
  • Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly. [Namekata K, et al. J Neurosci 2012;32(1):264-74]

    PubMed: 22219288
  • Acquired Resistance to BRAF Inhibition Can Confer Cross-Resistance to Combined BRAF/MEK Inhibition. [Gowrishankar K, et al. J Invest Dermatol 2012;132(7):1850-9]

    PubMed: 22437314
  • Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer. [Moestue SA, et al. Breast Cancer Res 2013;15(1):R16]

    PubMed: 23448424
  • Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. [Zhang Y, et al. Breast Cancer Res 2011;13(3):R52]

    PubMed: 21595894
  • The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. [Mukherjee B, et al. Neoplasia 2012;14(1):34-43]

    PubMed: 22355272
  • The PI3K/Akt pathway contributes to arenavirus budding. [Urata S, et al. J Virol 2012;86(8):4578-85]

    PubMed: 22345463
  • Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39. [Kong D, et al. Eur J Cancer 2010;46(6):1111-21]

    PubMed: 20129775
  • Targeting metastatic castration-resistant prostate cancer: mechanisms of progression and novel early therapeutic approaches [Cereda V Expert Opin Investig Drugs 2014;10.1517/13543784.2014.885950]

    PubMed: 24490883
  • Inactivation of AKT Induces Cellular Senescence in Uterine Leiomyoma. [Xu X, et al. Endocrinology 2014;155(4):1510-9]

    PubMed: 24476133
  • Lapatinib and Obatoclax kill tumor cells through blockade of ERBB1/3/4 and through inhibition of BCL-XL and MCL-1. [Cruickshanks N, et al. Mol Pharmacol 2012;81(5):748-58]

    PubMed: 22357666
  • Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway. [Kumandan S, et al. Cancer Lett 2013;329(2):236-42]

    PubMed: 23200669
  • Targeted Inhibition of FAK, PYK2 and BCL-XL Synergistically Enhances Apoptosis in Ovarian Clear Cell Carcinoma Cell Lines [Yoon H PLoS One 2014;9(2):e88587]

    PubMed: 24523919
  • Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 has a therapeutic potential and sensitizes cisplatin in nasopharyngeal carcinoma. [Yang F, et al. PLoS One 2013;8(3):e59879]

    PubMed: 23533654
  • Modulators of Sensitivity and Resistance to Inhibition of PI3K Identified in a Pharmacogenomic Screen of the NCI-60 Human Tumor Cell Line Collection. [Kwei KA, et al. PLoS One 2012;7(9):e46518]

    PubMed: 23029544
  • Quantitative 31 P HR-MAS MR spectroscopy for detection of response to PI3K/mTOR inhibition in breast cancer xenografts. [Esmaeili M, et al. Magn Reson Med 2013;10.1002/mrm.24869]

    PubMed: 23878023
  • (18)F-FDG Is a Surrogate Marker of Therapy Response and Tumor Recovery after Drug Withdrawal during Treatment with a Dual PI3K/mTOR Inhibitor in a Preclinical Model of Cisplatin-Resistant Ovarian Cancer. [Lheureux S, et al. Transl Oncol 2013;6(5):586-95]

    PubMed: 24151539
  • Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma. [Rahman M, et al. Hum Pathol 2012;43(12):2197-206]

    PubMed: 22705003
  • Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. [Zhan HX, et al. J Surg Oncol 2012;106(8):972-80]

    PubMed: 22711648
  • Phosphoproteomic analysis identifies activated MET-axis PI3K/AKT and MAPK/ERK in lapatinib-resistant cancer cell line. [Lee YY, et al. Exp Mol Med 2013;45:e64]

    PubMed: 24263233
  • An Isogenic Cell Panel Identifies Compounds That Inhibit Proliferation of mTOR-Pathway Addicted Cells by Different Mechanisms. [Lorenza Wyder Peters, et al. Journal of Biomolecular Screening 2013;19(1):131-44]

    PubMed: 23954931
  • Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. [Lemke J ,et al. Cell Death Differ 2013;10.1038/cdd.2013.179]

    PubMed: 24362439
  • Combination of TNF-α and Graphene Oxide Loaded BEZ235 to Enhance Apoptosis of PIK3CA Mutant Colorectal Cancer Cells [Yuhua Cao, et al. Journal of Materials Chemistry B 2013;5602-5610]

  • Signatures of drug sensitivity in nonsmall cell lung cancer. [Gong HC, et al. Int J Proteomics 2011;2011:215496]

    PubMed: 22091388

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Related PI3K 阻害剤

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    Ridaforolimus (Deforolimus, MK-8669) は、0.2nMのIC50による選択的なmTOR阻害剤です。

  • PI-103

    PI-103は、強力な、細胞透過性、ATP競争的クラスI PI3K阻害剤で、DNA-PK、 p110α、 mTORC1、 PI3-KC2β、 p110δ、 mTORC2、 p110β、p110γ に作用すると、IC50 がそれぞれ 2 nM、 8 nM、 20 nM、26 nM、 48 nM、 83 nM、 88 nM 、150 nMになる。

  • Rapamycin (Sirolimus)

    Rapamycin (Sirolimus) は、特定のmTOR阻害剤で、IC50 が ~0.1 nMです。

  • Temsirolimus (CCI-779, NSC 683864)

    Temsirolimus (CCI-779, NSC 683864)は、特定のmTOR阻害剤で、IC50 が 1.76 μM。

  • GDC-0941

    GDC-0941は、PI3Kα、PI3Kβ、PI3KδとPI3Kγの強力な阻害剤で、IC50 がそれぞれ 3 nM、 33 nM、 3 nM、75 nMです。

  • ZSTK474

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  • KU-55933 (ATM Kinase Inhibitor)

    KU-55933 (ATM Kinase Inhibitor)は、強力で特定の毛細血管拡張性運動失調突然変異するキナーゼ(ATM)阻害剤で、IC50 と Kiがそれぞれ13 nM 、2.2 nMになる。

  • LY294002

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