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| 25mg |
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| 50mg |
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| 100mg |
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Purity: ≥98%
CZ415 is a potent, cell-permeable (Kd app = 6.9 nM), and ATP-competitive mTOR inhibitor with high selectivity over any other kinase (IC50 = 14.5 nM IC50 for pS6RP and 14.8 nM for pAKT). It also has excellent pharmacokinetic properties, including moderate clearance and good oral bioavailability. The next step in CZ415 research should be in vivo tests. The molecule CZ415 is the best choice for studying the pathophysiological function of mTOR in vivo through pharmacological means. CZ415 exhibits no potential for genotoxicity and has excellent cell permeability.
| Targets |
mTOR (pIC50 = 8.07 nM); mTORC1; mTORC2
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|---|---|
| ln Vitro |
Inhibition of phosphorylation for both downstream targets results in 14.5 nM IC50 for pS6RP and 14.8 nM for pAKT. The immunosuppressive effect of CZ415 is assessed by detecting secreted IFN after 18 hours in stimulated human whole blood; the resulting IC50 is 226 nM. In a whole-cell patch-clamp assay in HEK293 cells, the activity of CZ415 against the human cardiac ion channel hERG is evaluated as a predictor for cardiotoxicity, with an IC50 of 48 M[1].
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| ln Vivo |
CZ415 is a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis (CIA) model. The pharmacokinetic (PK) profile of CZ415 is evaluated in rats for complete characterization and to allow for better dose predictions. After a 1 mg/kg intravenous bolus and a 3 mg/kg oral dose, the PK and oral bioavailability are assessed. The observed plasma clearance, which equates to 45% of the liver's blood flow, indicates that the animal's bloodstream is continuously circulating at levels that are adequate for the free compound. With a Tmaxmax of 0.5 hours, oral uptake is quick, and bioavailability F = 44% suggests very good gut absorption[1].
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| Cell Assay |
For the pS6RP S240/244 assay or the pAKT S473 assay, cells are seeded in a 96-well U-bottom plate at a density of 4x104 cells per well in 90 µLof DMEM containing 2% FCS. In order to promote cell adhesion, the plate is next placed in a humid incubator (37°C, 5% CO2). CZ415: n=2, 8 points at a dilution of 1:3, 3 µM starting concentration. 1 μM PI-103 (n=8) was used as a positive control. Controlling the negative: DMSO (n=8). The cells are then given 10 µL of a 10x compound concentration in 1% DMSO/99% (DMEM with 2% FCS), followed by a two-hour humid incubator incubation period (37 °C, 5% CO2). Adding 10 μL of 5x Complete Lysis Buffer and gently shaking the cells at 4°C for 15 minutes lyses the cells.
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| Animal Protocol |
Mice: The phosphorylation levels of S6 ribosomal protein and Akt, both of which are downstream targets of mTOR, are evaluated for dose-dependent changes to ascertain the effects of CZ415 on its pharmacological target. Mice receive oral doses of CZ415 at 1, 3, and 10 mg/kg, 1 hour prior to an anti-CD3 stimulus. Spleens are removed and their pS6RP and pAKT levels are measured 15 minutes after stimulation. After compound administration, a dose-related significant inhibition of Akt and S6RP phosphorylation is seen. In particular, 1 and 3 mg/kg of CZ415 were able to completely inhibit the S6RP phosphorylation that was brought on by anti-CD3 stimulation, and 10 mg/kg also reduced the levels of constitutive phosphorylation as measured in the control group.
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| References |
| Molecular Formula |
C22H29N5O4S
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|---|---|
| Molecular Weight |
459.561763525009
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| Exact Mass |
459.194
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| Elemental Analysis |
C, 57.50; H, 6.36; N, 15.24; O, 13.93; S, 6.98
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| CAS # |
1429639-50-8
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| Related CAS # |
1429639-50-8
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| Appearance |
Solid powder
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| SMILES |
O=C(NCC)NC1=CC=C(C2=NC(N3[C@@H](C)COCC3)=C4C(C(C)(C)S(C4)(=O)=O)=N2)C=C1
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| InChi Key |
IZLPVLBNRGPOHA-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C22H29N5O4S/c1-5-23-21(28)24-16-8-6-15(7-9-16)19-25-18-17(13-32(29,30)22(18,3)4)20(26-19)27-10-11-31-12-14(27)2/h6-9,14H,5,10-13H2,1-4H3,(H2,23,24,28)/t14-/m0/s1
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| Chemical Name |
(S)-1-(4-(7,7-dimethyl-4-(3-methylmorpholino)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea
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| Synonyms |
CZ415; CZ-415; CZ 415
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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 |
| 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) |
DMSO: ~91 mg/mL (198.0 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1760 mL | 10.8800 mL | 21.7599 mL | |
| 5 mM | 0.4352 mL | 2.1760 mL | 4.3520 mL | |
| 10 mM | 0.2176 mL | 1.0880 mL | 2.1760 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.
MS-based kinase-binding profile of3 (CZ415)across a set of protein kinases identified from mixed human cell-line lysates (285 kinases identified).
Activity of3in cellular assays: (A) Dose-dependent inhibition of S6RP phosphorylation in HEK293T after 2 h treatment of3, normalized to total S6RP levels. IC50= 14.5 nM (95% CI 11.5 to 18.3 nM,n= 4). (B) Dose-dependent inhibition of Akt phosphorylation in HEK293T after 2 h treatment of3, normalized to total Akt levels.ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
Time-dependent plasma concentration of3after intravenous bolus (iv, circle) and oral solution (po, square) administration to rats. Rats were dosed at 1 mg/kg (iv,n= 3) or 3 mg/kg (po,n= 3). Vehicle: 5% DMSO/95% (10% Kleptose). Compound3in a mouse CIA model. (A) Clinical arthritis score, all paws (Scored 0–5).ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
Compound3in anti-CD3 mouse model. (A) pS6RP levels (normalized to total S6RP) measured in spleens of compound treated as compared to disease vehicle group (p< 0.01 for 1 mg/kg of3;p< 0.001 for 3 and 10 mg/kg of3; one outlier removed in normal control and disease vehicle group). (B) Exposure response fit: pS6RP levels at terminal exposure. EC500.22 μM (95% CI 0.15 to 0.32 μM). (C) pAkt levels (normalized to total Akt) measured in spleens of compound treated as compared to disease vehicle group (p< 0.001 for 1, 3, and 10 mg/kg of3). (D) Exposure response fit: pAkt levels at terminal exposure. EC500.055 μM (95% CI 0.048 to 0.065 μM).ACS Med Chem Lett.2016 Jun 10;7(8):768-73. |
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