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BEZ235 (NVP-BEZ235)PI3K/mTOR inhibitor,ATP-competitve

BEZ235 (NVP-BEZ235)

Catalog No. A8246
Size Price Stock Qty
100mg $88.00 In stock
500mg $280.00 In stock

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Sample solution is provided at 25 µL, 10mM.

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Chemical structure

BEZ235 (NVP-BEZ235)

Related Biological Data

BEZ235 (NVP-BEZ235)
NVP-BEZ235 (0.2 μM) inhibits phosphorylation of the mammalian target of rapamycin (mTOR) target 4EBP1 in both monolayer and spheroid cultures. Lysates were prepared after 24h of treatment and subjected to Western blotting using the indicated antibodies.

Related Biological Data

BEZ235 (NVP-BEZ235)

Related Biological Data

BEZ235 (NVP-BEZ235)

Biological Activity

Description BEZ235 (NVP-BEZ235) is a dual ATP-competitive inhibitor of PI3K and mTOR for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM/5 nM/7 nM/75 nM/6 nM, respectively.
Targets p110α p110γ p110δ p110β ATR  
IC50 4 nM 5 nM 7 nM 75 nM 21 nM  

Protocol

Cell experiment: [1]

Cell lines

MOLT-4 and CEM-R cells

Preparation method

The solubility of this compound in DMSO is <10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

500 nM, for cell cycle inhibition 200 nM, 16 hours for pRb decrease

Applications

Flow cytometric analysis of PI-stained T-ALL cells treated with BEZ235 for 16 hours documented an increase in G0/G1 phase cells and a concomitant decrease in S and G2-M phases in both MOLT-4 and CEM-R cell lines. A decrease in the amount of Ser807/811 pRb was detected in MOLT-4 and CEM-R cells treated with 200 nmol/L NVP-BEZ235 for 16 hours, whereas total pRb levels remained unchanged.

Animal experiment: [2]

Animal models

Female athymic nude-Foxn1nu mice injected with BT474-VH2 cells

Dosage form

Oral administration, 40 mg/kg, once daily for 21 days

Application

The antitumor activity of BEZ235 was studied in a xenograft model derived from HER2-amplified BT474 breast cancer cells engineered to express either the H1047R hotspot mutation or the empty vector (pBABE). BEZ235 treatment resulted in suppressed tumor growth. The H1047R-overexpressing tumors responded better to the BEZ235 treatment when compared with mock controls.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Chiarini F, Grimaldi C, Ricci F, et al. Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against T-cell acute lymphoblastic leukemia. Cancer research, 2010, 70(20): 8097-8107.

[2] Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer research, 2008, 68(19): 8022-8030.

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Chemical Properties

Cas No. 915019-65-7 SDF Download SDF
Chemical Name 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
Formula C30H23N5O M.Wt 469.55
Solubility Limited solubility Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Background

BEZ235 is an imidazoquinoline derivative inhibiting both PI3K and mTOR kinases with low nanomolar IC50s. It was well tolerated in preclinical animal studies as well as in clinical trials with manageable gastrointestinal side-effects[1, 2]. It competes with ATP by binding to the ATP-binding site of kinases and reversibly reduces enzyme activity, resulting in growth arrest of tumor cells in G1 phase[1]. Besides the inhibition of cell growth, BEZ235 blocks VEGF-induced angiogenesis[3]. It may also inhibit DNA-PKcs[4].

BEZ235 has shown potential anti-tumor activity both in vitro and in vivo. It inhibited growth of multiple cancer cell lines independently of mutation status in PI3K pathway[5]. In xenograft mice models, it blocked PI3K signaling and showed antitumor activity[1, 5]. Combination study demonstrated that it enhances the efficacy of temozolomide[1].

Clinical data shows anti-tumor activity of BEZ235 treatment, especially in cancer patients with deregulated PI3K signaling pathway. This compound is currently under investigation in multiple clinical trials either as monotherapy or in combination with other agents.

References:
1. Maira SM, Stauffer F, Brueggen J 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: 1851-1863.
2. Markman B, Tabernero J, Krop I et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23: 2399-2408.
3. Schnell CR, Stauffer F, Allegrini PR et al. Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 2008; 68: 6598-6607.
4. Mukherjee B, Tomimatsu N, Amancherla K et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 2012; 14: 34-43.
5. Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 2008; 68: 8022-8030.