Cat. No. Name Size Price Add Cart
KI0178NVP-BEZ23550 mg$180
NVP-BEZ235100 mg$272

Chemical Characteristic

Product NameNVP-BEZ235
SynonymsBEZ235
CAS No.915019-65-7
Molecular Weight 469.55
FormulaC30H23N5O
Chemical Name2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)phenyl)propanenitrile
SmilesC(#N)C(C)(c1ccc(cc1)n1c2c(cnc3c2cc(cc3)c2cnc3c(c2)cccc3)n(c1=O)C)C
Chemical Structure

Biological activities

NVP-BEZ235 is a novel dual phosphatidylinositol 3-kinase (P13K)/mammalian target of rapamycin (mTOR) inhibitor in gliomas. NVP-BEZ235 inhibits PI3K and mTOR kinase activity by binding to the ATP binding cleft of enzymes, with IC50 of 4, 76, 7, 5, and 21 nM against p110α, p110β, p110γ, p110δ, and mTOR, respectively. NVP-BEZ235 suppresses glioma cell proliferation with IC50 values in the low nanomolar range by specifically inhibiting the activity of target proteins including Akt, S6K1, S6, and 4EBP1 in the PI3K/ Akt/mTOR signaling pathway. NVP-BEZ235 treatment of glioma cell lines leads to G1 cell cycle arrest and induces autophagy. NVP-BEZ235 antagonizes PI3K and mTOR signaling and induces cell cycle arrest, down-regulation of VEGF, and autophagy. [1] In NVP-BEZ235 treated samples, the IC50 for Ser473-P-Akt is 6.4 fold higher than that of phospho-S6 (p-S6) (77 nM compared to 12 nM). And the IC50 value for NVP-BEZ235 in BT474 cells is approximately 15 nM. NVP-BEZ235 (100 nM) treatment reduces phosphorylation of both AKT473 and S6240/244, which is accompanied by an increase in the phosphorylation of ERK in control cells, but not in PTEN knockdown cells. BT474 cells treated with NVP-BEZ235 exhibit a decreased mobility shift, stabilization of IRS1, and increase IRS1 tyrosine phosphorylation. NVP-BEZ235 suppresses the PI3K-mTOR axis driven by activating mutations in the PI3K pathway in trastuzumab and lapatinib resistant cells. NVP-BEZ235 works equally well at repressing the activity of both wild-type (WT) phosphatidylinositol 3-kinase (P13K)CA or the two mutant forms E545K and H1047R with IC50s of 4, 4.6 and 5.7 nM, respectively. [2] Multiple myeloma (MM) cell lines exhibit dose- and time-dependent decreased viability after exposure to NVP-BEZ235. In addition, NVP-BEZ235 is able to target MM cells in the presence of exogenous interleukin-6, insulin-like growth factor-1, stromal cells, or osteoclasts, which are known to protect against various anti-MM agents. NVP-BEZ235 treatment decreases the amplitude of transcriptional signatures previously associated with myc, ribosome, and proteasome function, as well as high-risk MM and undifferentiated human embryonic stem cells. [3] NVP-BEZ235 inhibits p110a-H1047R and p110a-E545K, with IC50s of 4.6 and 5.7 nM. NVP-BEZ235 specifically blocks the PI3K pathway in cells. And NVP-BEZ235 also possesses strong antiproliferative activity. [4] In vivo, NVP-BEZ235 significantly prolongs the survival of tumor-bearing animals without causing any obvious toxicity. In an intracranial model, the tumor volume after 4 weeks reaches ∼110 mm3 in control tumors, whereas the animals treated with NVP-BEZ235 at 25 and 45 mg/kg show tumor volumes of 70 and 30 mm3, respectively. [1] In vivo xenograft studies reveal significant reduction in tumor burden and survival in NVP-BEZ235-treated human MM tumor-bearing mice. [3] The in vivo tumor growth inhibition of NVP-BEZ235 activity is dose dependent, and the observed effect on S473P-Akt levels correlates with the amount of NVP-BEZ235 present in the tumor tissue. [4]

Protocols

NVP-BEZ235 is dissolved in DMSO to a concentration of 10 mM, stored at -20°C, and further diluted to an appropriate final concentration in DMEM at the time of use. [1]

References

[1] Liu TJ, et al. NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther. 2009, 8(8): 2204-2210.
[2] Eichhorn PJ, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008, 68(22): 9221-9230.
[3] McMillin DW, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009, 69(14): 5835-5842.
[4] Maira SM, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008, 7(7): 1851-1863.

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