product name CZ415
Description: CZ415, a potent, cell-permeable (Kd app = 6.9 nM), ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase (IC50 = 14.5 nM IC50 for pS6RP and 14.8 nM for pAKT) and very good pharmacokinetic properties which include moderate clearance and good oral bioavailability showed suitability of CZ415 for progression to in vivo studies. CZ415 represents an ideal molecule for the pharmacological investigation of mTOR pathophysiological role in vivo. CZ415 shows no genotoxic potential and has very good cell permeability.
References: ACS Med Chem Lett. 2016 Jun 10;7(8):768-73.
459.56
Formula
C22H29N5O4S
CAS No.
1429639-50-8
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 91 mg/mL (198.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: CZ415 shows no genotoxic potential and has very good cell permeability. Treatment of CZ415 leads to inhibition of phosphorylation for downstream targets of mTORC1 and mTORC2(IC50=14.5 nM for pS6RP and IC50=14.8 nM for pAKT). The immunosuppressive effect of CZ415 is measured by detecting secreted IFNγ after 18 h in stimulated human whole blood, and the resulting IC50 was 226 nM. CZ415 shows no genotoxic potential. It is neither mutagenic in a bacterial mutation assay (Ames test) nor does it show genotoxicity in the mouse lymphoma assay (MLA), in either the presence or absence of rat-liver S9 mix. Kinase Assay: IC50 & Target: 14.5 nM (pS6RP), 14.8 nM (pAKT), 226 nM (IFNγ) Cell Assay: Cells are seeded in 90 µL DMEM containing 2% FCS at 4×104 cells/well (for pS6RP S240/244 assay) or 8×104 cells/well (for pAKT S473 assay) in a 96well U-bottom plate. The plate is then incubated for 1h in a humidified incubator (37ºC, 5% CO2) to allow cells to adhere. CZ415: 3 µM start, 8 points 1:3 dilution steps, n=2. Positive control: 1 μM PI-103 (n=8). Negative control: DMSO (n=8). 10 µL of 10x compound concentration in 1% DMSO/99% (DMEM 2% FCS) are added to the cells followed by 2 h incubation in a humidified incubator (37ºC, 5% CO2). Cells are lysed by addition of 10 μL 5x Complete Lysis Buffer and gentle shaking at 4°C for 15 min. |
|---|---|
| In Vivo | In vivo studies show that CZ415 has moderate clearance and good oral bioavailability. In an anti-CD3 mouse model CZ415 efficiently inhibits mTOR downstream signaling and, in a CIA mouse model, shows significant antiinflammatory effects. With its extraordinary selectivity, drug-like properties and proven efficacy in vivo, CZ415 represents an ideal molecule for the pharmacological investigation of mTOR pathophysiological role in vivo. |
| Animal model | Male SD rats |
| Formulation & Dosage | Formulated in 5% DMSO/95% (10% Kleptose in saline); 1 mg/kg; i.v. injection |
| References | ACS Med Chem Lett. 2016 Jun 10;7(8):768-73. |
