Dactolisib

SKU: orb1305985

Description

Dactolisib (BEZ235) is a potent, orally active dual inhibitor of PI3K and mTOR kinase, with low nanomolar IC50 values against all PI3K isoforms and mTOR. It is widely used in preclinical research to investigate the PI3K/AKT/mTOR signaling pathway in cancer models, both in vitro and in vivo.

Research Area

Cell Biology, Molecular Biology, Signal Transduction

Key Properties

• CAS Number: 915019-65-7
• MW: 469.54
• Purity: 99.85% (May vary between batches)
• Formula: C₃₀H₂₃N₅O
• SMILES: O=C1N(C=2C=3C(N=CC2N1C)=CC=C(C3)C4=CC5=C(N=C4)C=CC=C5)C6=CC=C(C(C#N)(C)C)C=C6
• Target: ATM/ATR,mTOR,PI3K,Autophagy
• Solubility: DMSO:1 mg/mL (2.13 mM);H2O:< 0.1 mg/mL (insoluble)

Bioactivity

• Target IC50:
  p110α-H1047R:4.6 nM|p110β:75 nM (cell free)|p110γ:5 nM (cell free)|p110α-E545K:5.7 nM|p110α:4 nM (cell free)|p110δ:7 nM (cell free)|mTOR (p70S6K):6 nM (cell free)
• In Vivo:
  In the absence of inhibitors, the weight of the chamber, as well as levels of the endothelial cell marker Tie-2, were significantly increased in the presence of VEGF. Both effects were significantly inhibited in a dose-dependent manner when the mice were treated with NVP-BEZ235 given p.o. twice a day at 20 mg/kg or once at 30 mg/kg, showing the specificity of the angiogenic response driven by the VEGF . NVP-BEZ235–treated adenomas (20 mg/kg) showed pronounced vacuolation of the cytoplasm when compared with PEG-treated animals. Vacuoles appeared even more prominent at the 30 and 45 mg/kg doses .
• In Vitro:
  Dactolisib (BEZ235) shows slightly lower activity against the β paralogue (IC50: 75 nmol/L). NVP-BEZ235 (250 nmol/L) was able to reduce IGF-I-induced S473P-Akt levels below the limit of detection, whereas the phosphorylation of the p85 binding site on IGF-IR (Y1316) was not altered . BEZ235 provoked a more profound effect with an IC50 value of 1.8 nmol/L and cytostasis was obtained at 10 nmol/L. Moreover, at a concentration of 100 nmol/L, the BrdUrd uptake was less than the one observed in starved, VEGF-untreated cells, indicative of cell death induction .
• Cell Research:
  The proliferation of BON1, QGP1, and αT3 cells after treatment was measured with the WST-1 colorimetric assay. Cell proliferation in 3D spheroids was measured with the CellTiter-Glo Cell Viability Assay according to the manufacturer's recommendations. Apoptosis was measured by assessing the activity of caspase-3/7 using the Caspase-Glo 3/7 Assay Kit. BON1 cells and QGP1 cells were transfected with scrambled or anti-DEFB1 siRNA as above, and 24 hours later treated with NVP-BEZ235 or DMSO for an additional 24 hours. Caspase-3/7 activity was then assessed with a proluminescent caspase-3/7 substrate, which contains the tetrapeptide sequence DEVD. Luminescence was measured with a luminometer .
• Animal Research:
  Three doses of NVP-BEZ235 were tested in MENX rats: 20, 30, and 45 mg/kg. As the two higher doses caused a weight loss >10% after 10 days of treatment, the dose of 20 mg/kg was 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) were treated for 14 days with NVP-BEZ235 (20 mg/kg) or placebo (PEG) administered daily per oral gavage. The side effect of the drug we observed was mild diarrhea in the last days of the treatment (4/8 rats). Being this our first in vivo study of spontaneous rat pituitary adenomas, functional/molecular changes in the tumors were considered more objective and measurable endpoints (primary endpoints) compared to the size and/or survival (secondary endpoints) .

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Dactolisib, BEZ 235, BEZ235, BEZ-235, Autophagy, ATM, ATR, Inhibitor, Mammalian target of Rapamycin, NVP-BEZ235, NVP-BEZ-235, NVP-BEZ 235, p110α, p110γ, p110δ, inhibit, mTOR (p70S6K), mTOR, PI3K, Phosphoinositide 3-kinase

Compound Identifiers

PubChem CID

11977753