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Purity: ≥98%
CZC24832 is a novel, potent and highly selective inhibitor of PI3Kγ (phosphoinostide 3-kinase γ) with a potential for treatment for inflammatory and autoimmune diseases (e.g. RA). It has an IC50 of 27 nM, exhibits >100-fold selectivity for PI3Kγ over PI3Kα and PI3Kδ, and inhibits PI3Kγ with a 10-fold preference over PI3Kγ .
| Targets |
PI3Kβ (IC50 = 1.1 μM); PI3Kδ (IC50 = 8.194 μM); PI3Kγ (IC50 = 27 nM)
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| ln Vitro |
CZC24832 is active in PI3Kγ-dependent cellular C5a-induced AKT Ser473 phosphorylation (IC50=1.2 μM) and N-formyl-methionine-leucinephenylalanine (fMLP)-induced neutrophil migration assays (IC50=1.0 μM)[1].
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| ln Vivo |
CZC24832 shows suitable pharmacokinetic properties including low clearance (0.84 L per h per kg body weight) and high oral bioavailability (37%), thus allowing further characterization of the inhibitor in rodent models of inflammation. CZC24832 exhibits a dose-dependent decrease in granulocyte recruitment in an IL-8-dependent air pouch model (80% inhibition at 10 mg/kg body weight), which is consistent with the level of inhibition seen in PI3K-null mice. The amount of bone and cartilage destruction in mice treated orally with 10 mg CZC24832 per kg body weight twice per day is significantly reduced (53% less according to histopathological analysis), as are the majority of clinical parameters (38% less)[1].
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| Enzyme Assay |
Competition binding assays using the LK matrix are performed essentially as described above but adapted to a 384-well format. 0.25 mg of cell lysate and 2.5 μL of beads are used per well. Compounds from the screening library including reference compounds as standards are added at 40 μM final concentration from 50× DMSO stocks. Each plate contains 15 positive and 17 negative controls. After 2 hrs binding at 4 °C, the non-bound fraction is removed by washing the beads with lysis buffer. Proteins retained on the beads are eluted in SDS sample buffer and spotted on nitrocellulose membranes (400 nL/spot) using an automated pin tool liquid transfer. After drying, the membranes are rehydrated in 20% ethanol, and processed for detection with specific antibodies as indicated, followed by incubation with a labeled secondary antibody for visualization. Spot intensities are quantified using a scanner and percentage inhibition is calculated using positive and negative controls as 100% and 0% inhibition, respectively.
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| Cell Assay |
RAW264.7 or THP-1 cells are starved for 2.5 h in serum-free medium before CZC24832 (0.1, 1, 10 and 100 μM) incubation for 30 min at 37°C. Then, THP-1 cells are stimulated with either insulin (1 uM, 10 min) or CSF (50 g/mL, 5 min) at 37°C before being lysed on ice. RAW264.7 cells are then stimulated for 3 min with C5a at a concentration of 0.6 μM. The iBlot system is used to identify AKT phosphorylation (Ser473)[1].
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| Animal Protocol |
Mice: Pharmacokinetics and oral bioavailability of CZC24832 are investigated in male Wistar rats following administration of a single intravenous (0.2 mg per kg body weight) or oral dose (10 mg per kg body weight). For oral gavage, 0.5% (w/v) carboxymethyl cellulose in water is the dosing agent. 10% (v/v) DMSO in 30% (v/v) PEG-400 serves as the intravenous dosing vehicle. For the preparation of plasma samples, heparin blood is withheld retro-orbitally from mice or sublingually from rats. For the HPLC-MS/MS CZC24832 analysis, these are homogenized with 10% (v/v) water and three volumes of acetonitrile.
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| References |
| Molecular Formula |
C15H17FN6O2S
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|---|---|
| Molecular Weight |
364.3979
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| Exact Mass |
364.4
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| Elemental Analysis |
C, 49.44; H, 4.70; F, 5.21; N, 23.06; O, 8.78; S, 8.80
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| CAS # |
1159824-67-5
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| Related CAS # |
1159824-67-5
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| Appearance |
Solid powder
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| SMILES |
CC(C)(C)NS(=O)(=O)C1=CN=CC(=C1)C2=CN3C(=NC(=N3)N)C(=C2)F
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| InChi Key |
RXRZPHQBTHQXSV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H17FN6O2S/c1-15(2,3)21-25(23,24)11-4-9(6-18-7-11)10-5-12(16)13-19-14(17)20-22(13)8-10/h4-8,21H,1-3H3,(H2,17,20)
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| Chemical Name |
5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide
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| Synonyms |
CZC24832; CZC 24832; CZC-24832
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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: ~5 mg/mL warming (~13.7 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
0.5% CMC: 30 mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7442 mL | 13.7212 mL | 27.4424 mL | |
| 5 mM | 0.5488 mL | 2.7442 mL | 5.4885 mL | |
| 10 mM | 0.2744 mL | 1.3721 mL | 2.7442 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.
Design and characterization of CZC24832, a selective PI3Kγ inhibitor. Nat Chem Biol, 2012, 8(6), 576-582. |
Cellular activity profile of CZC24832 |
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