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Purity: ≥98%
Dactolisib tosylate (formerly also known as NVP-BEZ235 tosylate and BEZ-235 tosylate) is an ATP-competitive and dual inhibitor of PI3K (phosphatidylinositol 3-kinase) and mTOR for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM /5 nM /7 nM /75 nM /6 nM in cell-free assays, respectively. Pituitary adenomas that are not functioning exhibit strong anticancer efficacy when treated with dactolisib.
| Targets |
p110α (IC50 = 4 nM); p110α-H1047R (IC50 = 4.6 nM); p110α-E545K (IC50 = 5.7 nM); p110γ (IC50 = 5 nM); p110δ (IC50 = 7 nM); p110β (IC50 = 75 nM); mTOR (IC50 = 20.7 nM); mTORC1; mTORC2; Autophagy
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| ln Vitro |
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| ln Vivo |
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.
Dactolisib (BEZ235, NVP-BEZ 235) Is an Orally Available PI3K Inhibitor with Well-Tolerated Antitumor Activity [1] The pharmacokinetic properties of NVP-BEZ235 were originally evaluated in PC3M tumor-bearing nude mice. At a dose of 50 mg/kg, NVP-BEZ235 appeared rapidly in plasma with a Cmax of 1.68 μmol/L at 0.5 h and a C24h of 0.03 μmol/L. In the tumor tissue, the Cmax attained was 2.05 nmol/g at 1 h (Tmax), which decreased to 0.23 nmol/g after 24 h (Fig. 5A). Dactolisib (BEZ235, NVP-BEZ 235) is eliminated relatively quickly from the liver. In vivo analysis of the S473P-Akt levels in the tumor tissue revealed that maximum inhibition was obtained 1 h after dosing (corresponding to the tumor Cmax), and persistent inhibition was observed still 16 h after treatment, with almost complete recovery to basal levels obtained in two of four tumors at 24 h after dose (Fig. 5B). Pharmacokinetic simulation based on this study revealed that steady-state levels would be achieved between 3 and 5 days, when dosing either at 50 mg/kg given daily or at 25 mg/kg given twice daily. Differences between the dosage regimens would reside in the predicted tumor peak levels (2.6 versus 1.6 nmol/g, respectively) whereas through levels would remain almost comparable (0.53 versus 0.60 μmol/L, respectively). Taking into consideration this pharmacokinetic simulation, chronic treatment of PC3M tumor-bearing animals was done at 25 mg/kg p.o. NVP-BEZ235 twice daily. Using this schedule, a statistically significant inhibition of tumor growth was observed, with a final T/C value of 22% after 10 days of treatment (Fig. 5C). The treatment was well tolerated as concluded from the nonstatistically significant effect of NVP-BEZ235 on body weight gain (Fig. 5C) and by the fact that none of the animals died during the course of the study. The antitumor effect was well correlated with the inhibition of S473P-Akt in the tumor tissue 1 or 18 h after the last dose detected either by Western blotting of tumor extracts or by immunostaining of tumor sections (Fig. 5D). Compound concentrations at these time points were 1.32 nmol/g at 1 h and 0.51 nmol/g at 18 h, close to the predicted values for steady-state peak levels (see above). |
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| Enzyme Assay |
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.
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| Cell Assay |
MOLT-4 and CEM-R cells; 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; 500 nM, for cell cycle inhibition 200 nM, 16 hours for pRb decrease.
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 BEZ235 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. BEZ235 is an mTORC1/2 catalytic inhibitor.
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| Animal Protocol |
Mice: The NVP-Dactolisib (BEZ235) powder is dissolved in NMP on sonication, and the remaining volume of polyethylene glycol 300 is added to a concentration of 5 mg/mL. The dosage is 10 mL/kg. For analysis, frozen tissues are minced, then homogenized in an equal volume of ice-cold PBS. After centrifugation, supernatants are then examined. The samples are then eluted over a 20-minute period at a flow rate of 1 mL/min with a linear gradient of 10% to 90% (v/v) acetonitrile in water containing 0.05% (v/v) trifluoroacetic acid. The compounds are identified by 340 nm UV absorbance, and peak heights from the external standard method are used to calculate concentrations[1].
Establishment of Xenograft Tumors, Efficacy Studies, Compound Preparation, and Analytics [1] Establishment of tumors, group randomization, tumor, and body weight recording during efficacy studies were described elsewhere. Antitumor activity is expressed as %T/C (mean increase of tumor volumes of treated animals divided by the mean increase of tumor volumes of control animals multiplied by 100) and/or as tumor regression (%Reg) calculated as [(mean tumor volume at the start of treatment - mean tumor volume) / (mean tumor volume at the start of treatment)] × 100. Data are presented as mean ± 1 SE. Comparisons between groups and vehicle control group were done using either one-way ANOVA or ANOVA on ranks followed by Dunnett's tests when data were respectively either normally distributed or not. For all tests, the level of significance was set at P < 0.05. Calculations were done using SigmaStat version 2.03. Dactolisib (BEZ235, NVP-BEZ 235) (free base) was formulated in NMP/polyethylene glycol 300 (10/90, v/v). Solutions (5 mg/mL) were prepared fresh each day of dosing as follows: the powder was dissolved in NMP on sonication, and the remaining volume of polyethylene glycol 300 was added. The application volume was 10 mL/kg. For analytics, frozen tissues were minced and then homogenized in an equal volume of ice-cold PBS using a Polytron homogenizer (IKA). After acetonitrile precipitation and centrifugation, supernatants were analyzed by reverse-phase high-performance liquid chromatography/UV on a Merck-Hitachi/LaChrom equipment including a Nucleosil 100-5 C18 column. Samples were then eluted with a linear gradient of 10% to 90% (v/v) acetonitrile in water containing 0.05% (v/v) trifluoroacetic acid over a period of 20 min at a flow rate of 1 mL/min. The compounds were detected by UV absorbance at 340 nm, and concentrations were determined by the external standard method using peak heights. |
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| References | ||
| Additional Infomation |
Dactolisib Tosylate is the tosylate salt form of dactolisib, an orally bioavailable imidazoquinoline targeting the phosphatidylinositol 3 kinase (PI3K) and the mammalian target of rapamycin (mTOR), with potential antineoplastic activity. Upon administration, dactolisib inhibits PI3K kinase and mTOR kinase in the PI3K/AKT/mTOR kinase signaling pathway, which may result in tumor cell apoptosis and growth inhibition in PI3K/mTOR-overexpressing tumor cells. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy. mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.[1] |
| Molecular Formula |
C37H31N5O4S
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|---|---|
| Molecular Weight |
641.75
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| Exact Mass |
641.21
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| Elemental Analysis |
C, 69.25; H, 4.87; N, 10.91; O, 9.97; S, 5.00
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| CAS # |
1028385-32-1
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| Related CAS # |
Dactolisib;915019-65-7; 1028385-32-1; 2319647-83-9 (HCl)
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| PubChem CID |
49803145
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
8.216
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
47
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| Complexity |
1080
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN(C1=C2C3=CC(C4=CC5=CC=CC=C5N=C4)=CC=C3N=C1)C(N2C6=CC=C(C=C6)C(C)(C#N)C)=O.CC7=CC=C(S(=O)(O)=O)C=C7
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| InChi Key |
FWURTHAUPVXZHW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H23N5O.C7H8O3S/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36;1-6-2-4-7(5-3-6)11(8,9)10/h4-17H,1-3H3;2-5H,1H3,(H,8,9,10)
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| Chemical Name |
4-methylbenzenesulfonic acid;2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-1-yl)phenyl]propanenitrile
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| Synonyms |
Dactolisib tosylate; NVP-BEZ 235 Tosylate; NVP-BEZ235-ANA; BEZ235 Tosylate; BEZ235 Tosylate; BEZ235 (Tosylate); Dactolisib (Tosylate); NVP-BEZ235-ANA; Dactolisib tosilate; Dactolisib tosylate [USAN]; UNII-U54GT9151S
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (1.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: NMP+polyethylene glycol 300 (10/90, v/v): 30mg/mL View More
Solubility in Formulation 3: 16.67 mg/mL (25.98 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5582 mL | 7.7912 mL | 15.5824 mL | |
| 5 mM | 0.3116 mL | 1.5582 mL | 3.1165 mL | |
| 10 mM | 0.1558 mL | 0.7791 mL | 1.5582 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 Modeled structures of compound31with PI3Kα and mTOR.ACS Med Chem Lett.2018 Feb 27;9(3):256-261. |
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 PC-3M xenograft model tumor growth curve and body weight change (%).ACS Med Chem Lett.2018 Feb 27;9(3):256-261. |
 Modeled structure of compound4with PI3Kα.
Inhibition of pAKT in MCF-7 cell at 1 μM concentration.ACS Med Chem Lett.2018 Feb 27;9(3):256-261. |
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