1. PI3K/Akt/mTOR
  2. PI3K
    mTOR

BEZ235 (Synonyms: NVP-BEZ235)

Cat. No.: HY-50673 Purity: 98.83%
Data Sheet SDS Handling Instructions

BEZ235 is a dual pan-class I PI3K and mTOR kinase inhibitor with IC50 of 4 nM/5 nM/7 nM/75 nM, and 6 nM for p110α/γ/δ/β and mTOR (p70S6K), respectively.

For research use only. We do not sell to patients.
BEZ235 Chemical Structure

BEZ235 Chemical Structure

CAS No. : 915019-65-7

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Customer Review

Other Forms of BEZ235:

    BEZ235 purchased from MCE. Usage Cited in: Nat Commun. 2017 Jun 8;8:15617.

    Immunoblot analysis of KRAS protein levels in parental (P) and resistant derivatives (R1 and R2) following 4 h treatment with the corresponding inhibitors Rapamycin, AZD2014, MLN0128, BEZ235 and 4EGI-1. Images are cropped for clarity from the same exposure of the same membrane.

    BEZ235 purchased from MCE. Usage Cited in: Leukemia. 2014 Sep;28(9):1819-27.

    Western blot analysis of human T-ALL cell lines treated for 24 hours using DMSO (vehicle control), 1 μM JQ1, 500 nM BEZ235, or both drugs in combination, using the indicated antibodies. Western blot analysis of these T-ALL cell lines following treatment with JQ1, BEZ235 or both drugs in combination reveals cooperative upregulation of BIM protein expression coupled to induction of apoptosis, as assessed by PARP cleavage.

    BEZ235 purchased from MCE. Usage Cited in: EBioMedicine. 2015 Nov 19;2(12):1944-56.

    SW620 xenograft tumors are treated with SB202190 and OSI027 individually or in combination. The effect on signaling by p38 (P-MK2 and P-Hsp27) and mTOR (P-S6K1 and P-AKT) is analyzed by immunoblot. SB202190 achieves on-target inhibition by diminishes phosphorylation of MK2 and Hsp27. OSI-027 blocks signaling by both mTORC1 and mTORC2 by decreases phosphorylation of S6K1 and AKT. When SB202190 and OSI-027 are used in combination, all three kinases, p38, mTORC1 and mTORC2 are potently inhibited.

    BEZ235 purchased from MCE. Usage Cited in: Oncotarget. 2017 Jul 11;8(28):45470-45483.

    Activity of PI3K/AKT/mTOR is monitored by examining phosphorylation of AKT-S473, AKT-T308, and S6 by western blotting.

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    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    BEZ235 is a dual pan-class I PI3K and mTOR kinase inhibitor with IC50 of 4 nM/5 nM/7 nM/75 nM, and 6 nM for p110α/γ/δ/β and mTOR (p70S6K), respectively.

    IC50 & Target

    IC50: 4 nM (p110α), 5 nM (p110γ), 7 nM (p110δ), 75 nM (p110β), 6 nM (mTOR)[1]

    In Vitro

    BEZ235 (NVP-BEZ235) potently inhibits PI3K in an ATP Competitive Manner. NVP-BEZ235 (250 nM) significantly reduced the phosphorylation levels of the mTOR activated kinase p70S6K. NVP-BEZ235 also leads to a reduction of S235/S236P-RPS6 levels with an IC50 of 6.5 nM, suggesting that NVP-BEZ235 can directly inhibit the mTOR kinase, as the kinase domain of mTOR is highly homologous to the one of class IA PI3K. The activity of NVP-BEZ235 against mTOR is confirmed using a biochemical mTOR K-LISA assay (IC50, 20.7 nM)[1]. The IC50s of NVP-BEZ235 for HCT116, DLD-1, and SW480 cell lines are 14.3±6.4, 9.0±1.5, and 12.0±1.6 nM, respectively[2].

    In Vivo

    BEZ235 (NVP-BEZ235) (45 mg/kg, p.o.) treatment induces colonic tumor regression in a GEM model for sporadic PIK3CA wild-type CRC[2]. NVP-BEZ235 (45 mg/kg) is administered to MENX rats (n=2 each group) by oral gavage and animals are sacrificed 1 or 6 hours after treatment. Immunostains for P-AKT and P-S6 show considerable reduction of the two proteins, and particularly of P-S6, 6 hours after administration of NVP-BEZ235 when compares with PEG-treated rats. At 6 hours after treatment, the pituitary adenomas of NVP-BEZ235-treated rats has a proteomic profile significantly different from the tumors of placebo-treated rats[3].

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT01856101 Cliniques universitaires Saint-Luc- Université Catholique de Louvain|Novartis Carcinoma Transitional Cell February 2013 Phase 2
    NCT01343498 SCRI Development Innovations, LLC|Novartis Malignant Solid Tumour April 2011 Phase 1
    NCT01453595 Memorial Sloan Kettering Cancer Center|Novartis Renal Cancer October 2011 Phase 1|Phase 2
    NCT01290406 Novartis Pharmaceuticals|Novartis Endometrial Cancer March 2012 Phase 2
    NCT01482156 Novartis Pharmaceuticals|Novartis Advanced Solid Tumors|Metastatic Breast Cancer|Metastatic Renal Cell Carcinoma January 2012 Phase 1
    NCT01658436 Novartis Pharmaceuticals|Novartis Pancreatic Neuroendocrine Tumors (pNET) November 2012 Phase 2
    NCT01690871 Novartis Pharmaceuticals|Novartis Malignant PEComa (Perivascular Epithelioid Cell Tumors) September 2012 Phase 2
    NCT00620594 Novartis Pharmaceuticals|Novartis Breast Cancer|Advanced Solid Tumors|Cowden Syndrome December 21, 2006 Phase 1
    NCT01495247 Novartis Pharmaceuticals|Novartis Inoperable Locally Advanced Breast Cancer|Metastatic Breast Cancer (MBC) January 2012 Phase 1|Phase 2
    NCT01756118 Johann Wolfgang Goethe University Hospital Acute Lymphoblastic Leukemia|Leukemia, Myelocytic, Acute|Chronic Myelogenous Leukemia With Crisis of Blast Cells June 2012 Phase 1
    NCT01717898 Charles Ryan|Novartis Pharmaceuticals|University of California, San Francisco Castrate-resistant Prostate Cancer Patients. January 2013 Phase 1|Phase 2
    NCT01628913 Novartis Pharmaceuticals|Novartis Pancreatic Neuroendocrine Tumors (pNET) October 2012 Phase 2
    NCT01195376 Novartis Pharmaceuticals|Novartis Advanced Solid Tumor October 2010 Phase 1
    NCT01288092 Novartis Pharmaceuticals|Novartis Metastatic Breast Cancer March 2012 Phase 2
    NCT01337765 Array BioPharma Unspecified Adult Solid Tumor, Protocol Specific|Solid Tumor July 2011 Phase 1
    NCT01634061 Novartis Pharmaceuticals|Novartis Castration-resistant Prostate Cancer September 2012 Phase 1
    NCT01471847 Novartis Pharmaceuticals|Novartis Locally Advance Breast Cancer (LABC)|Metastatic Breast Cancer (MBC) February 2012 Phase 1
    NCT01508104 University of Cincinnati|Novartis Cancer January 2012 Phase 1|Phase 2
    NCT01248494 Vanderbilt-Ingram Cancer Center Metastatic Breast Cancer November 2010 Phase 1
    NCT01285466 Novartis Pharmaceuticals|Novartis Metastatic or Locally Advanced Solid Tumors January 2011 Phase 1
    NCT01856101 Cliniques universitaires Saint-Luc- Université Catholique de Louvain|Novartis Carcinoma Transitional Cell February 2013 Phase 2
    NCT01343498 SCRI Development Innovations, LLC|Novartis Malignant Solid Tumour April 2011 Phase 1
    NCT01453595 Memorial Sloan Kettering Cancer Center|Novartis Renal Cancer October 2011 Phase 1|Phase 2
    NCT01290406 Novartis Pharmaceuticals|Novartis Endometrial Cancer March 2012 Phase 2
    NCT01482156 Novartis Pharmaceuticals|Novartis Advanced Solid Tumors|Metastatic Breast Cancer|Metastatic Renal Cell Carcinoma January 2012 Phase 1
    NCT01658436 Novartis Pharmaceuticals|Novartis Pancreatic Neuroendocrine Tumors (pNET) November 2012 Phase 2
    NCT01690871 Novartis Pharmaceuticals|Novartis Malignant PEComa (Perivascular Epithelioid Cell Tumors) September 2012 Phase 2
    NCT00620594 Novartis Pharmaceuticals|Novartis Breast Cancer|Advanced Solid Tumors|Cowden Syndrome December 21, 2006 Phase 1
    NCT01495247 Novartis Pharmaceuticals|Novartis Inoperable Locally Advanced Breast Cancer|Metastatic Breast Cancer (MBC) January 2012 Phase 1|Phase 2
    NCT01756118 Johann Wolfgang Goethe University Hospital Acute Lymphoblastic Leukemia|Leukemia, Myelocytic, Acute|Chronic Myelogenous Leukemia With Crisis of Blast Cells June 2012 Phase 1
    NCT01717898 Charles Ryan|Novartis Pharmaceuticals|University of California, San Francisco Castrate-resistant Prostate Cancer Patients. January 2013 Phase 1|Phase 2
    NCT01628913 Novartis Pharmaceuticals|Novartis Pancreatic Neuroendocrine Tumors (pNET) October 2012 Phase 2
    NCT01195376 Novartis Pharmaceuticals|Novartis Advanced Solid Tumor October 2010 Phase 1
    NCT01288092 Novartis Pharmaceuticals|Novartis Metastatic Breast Cancer March 2012 Phase 2
    NCT01337765 Array BioPharma Unspecified Adult Solid Tumor, Protocol Specific|Solid Tumor July 2011 Phase 1
    NCT01634061 Novartis Pharmaceuticals|Novartis Castration-resistant Prostate Cancer September 2012 Phase 1
    NCT01471847 Novartis Pharmaceuticals|Novartis Locally Advance Breast Cancer (LABC)|Metastatic Breast Cancer (MBC) February 2012 Phase 1
    NCT01508104 University of Cincinnati|Novartis Cancer January 2012 Phase 1|Phase 2
    NCT01248494 Vanderbilt-Ingram Cancer Center Metastatic Breast Cancer November 2010 Phase 1
    NCT01285466 Novartis Pharmaceuticals|Novartis Metastatic or Locally Advanced Solid Tumors January 2011 Phase 1
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 2.1297 mL 10.6487 mL 21.2974 mL
    5 mM 0.4259 mL 2.1297 mL 4.2595 mL
    10 mM 0.2130 mL 1.0649 mL 2.1297 mL
    Kinase Assay
    [1]

    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. Compounds 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 nL of test items (in 90% DMSO) and 5 μL reaction buffer [10 mM Tris-HCl (pH 7.5), 50 mM NaCl, 3 mM MgCl2, 1 mM DTT, and 0.05% CHAPS] 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. The reaction is started by the addition of 5 μL of 1 μM ATP prepared in the reaction buffer and ran for either 60 (for p110α, p110β, and p110δ) or 120 min (for p110γ) and subsequently terminated by the addition of 10 μL Kinase-Glo buffer. The plates are then read in a Synergy 2 reader for luminescence detection[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [2]

    BEZ235 (NVP-BEZ235) is dissolved in DMSO (10 mM) and stored, and then diluted with appropriate media (DMSO 0.1%) before use[2].

    HCT116 (PIK3CA mutant; kinase domain at H1047R), DLD-1 (PIK3CA mutant; helical domain at E545K), and SW480 (PIK3CA wild-type) human CRC cell lines (ATCC) and isogenic DLD-1 PIK3CA mutant and wild-type cells are maintained in DMEM with 10% FBS and 1× Penicillin/Streptomycin. Cells are plated at different initial densities (HCT116: 3,000 cells/well, DLD-1: 5,500 cells/well, SW480: 4,500 cells/well, DLD-1 PIK3CA mutant: 7,000 cells/well, and DLD-1 PIK3CA wild-type: 9,000 cells/well) to account for differential growth kinetics. After 16 hours, cells are incubated with increasing concentrations of BEZ235 (10, 100, 1000 nM), and 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. Cell viability after drug treatment is normalized to that of untreated cells also grown for 48 hours. IC50 values are calculated using 4 parameter nonlinear regression in GraphPad Prism 5[2]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [2][3]

    BEZ235 (NVP-BEZ235) is prepared in 10% 1-methyl-2-pyrrolidone/90% PEG 300 (Mice)[2].
    BEZ235 (NVP-BEZ235) is suspended in 1 volume of 1-methyl-2-pyrrolidone and 9 volumes of PEG300 (Rat)[3].

    Mice[2]
    Tumor-bearing Apc CKO mice are randomly assigned to treatment with either control vehicle alone (n=8) or 45 mg/kg body weight BEZ235 in 10% 1-methyl-2-pyrrolidone/90% PEG 300 (n=8) by daily oral gavage for 28 days. The treatment dose is chosen based on literature indicating that 40-50 mg/kg body weight BEZ235 effectively treats murine tumor models without adverse effects. Base on pharmacokinetic studies demonstrating maximal tissue concentration one hour after NVP-BEZ235 administration, tumor-bearing mice are sacrificed one hour after final treatment dose. Colonic tumor volume is assessed using calipers (width×length×height) and tumors are harvested for both western blot analysis and immunohistochemistry.
    Rat[3]
    MENX-affected rats used. Three doses of BEZ235 are tested in MENX rats: 20, 30, and 45 mg/kg. As the two higher doses causes a weight loss >10% after 10 days of treatment, the dose of 20 mg/kg is used for further studies. For MRI studies, MENX-affected rats at 7 to 8 months of age (with sizeable adenomas but still in good general health) are treated for 14 days with BEZ235 (20 mg/kg) or placebo (PEG) administered daily per oral gavage. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    469.54

    Formula

    C₃₀H₂₃N₅O

    CAS No.

    915019-65-7

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: 8.75 mg/mL

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    Purity: 98.83%

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    Product Name:
    BEZ235
    Cat. No.:
    HY-50673
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