AS-604850 is a selective, ATP-competitive PI3Kγ inhibitor with IC50 of 0.25, >20, >20, and 4.5 µM for the human recombinant γ, δ, β, and α isoforms, respectively. AS-604850 shows no notable activity against a wide array of protein kinases at 1 μM. AS-604850 inhibited MCP-1-mediated monocyte chemotaxis with an IC50 value of 21 µM and reduced RANTES-induced peritoneal neutrophil recruitment in a murine model of leukocyte chemotaxis with an ED50 value of 42.4 mg/kg.
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Source | PLoS One (2016). Figure 6. AS-604850 |
| Method | CCRF-CEM cells | |
| Cell Lines | resazurin reduction assay | |
| Concentrations | 50 μM | |
| Incubation Time | 3 days | |
| Results | We treated these cells with a p110γ-specific inhibitor, AS-604850, at dosing appropriate for in vitro cell based assays, both alone and in combination with CP-751,871 antibody on the premise that AS-604850 would block p110γ and CP-751,871 would block IGF1R-dependent p110α/β/δ |
| Cell Experiment | |
|---|---|
| Cell lines | HepG2 Ntcp and Huh7-Ntcp cells |
| Preparation method | Treating hepatocyte cultures with diluent (DMSO), 25 μM TLC, 250 μM TCDC, 50 μM GCDC, or 50 ng/ml Fas for 2-4 hours HepG2-Ntcp and treating Huh7-Ntcp cells with DMSO, 20 μM TLC, 75 μM TCDC or GCDC, 200 μM etoposide or 200 ng/ml TNFa plus 28 ng/ml actinomycin D for 2-4 hours. Using fluorescent staining to determine morphologically the number of apoptotic cells expressing as % of cells . Apoptosis is confirmed in human cell lines by determination of caspase-3/-7 activity and in rat hepatocytes by detection of the 17 kDa proteolytic cleavage fragment of caspase-3 by immunoblotting; equal protein loading is monitored by immunoblotting for actin. |
| Concentrations | 2.5 μM |
| Incubation time | 2 - 4 hours |
| Animal Experiment | |
|---|---|
| Animal models | RANTES (0.5 mg/kg in 200 ml saline) or thioglycollate (40 ml/kg) are intraperitoneally injected to C3H mice to induce peritonitis mouse models |
| Formulation | AS-604850 is dissolved in vehicle (0.5% carboxymethylcellulose/0.25% Tween-20) and adjusted the solution to 10 mL/kg of body weight. |
| Dosages | 0, 1, 3, 10 or 30 mg/kg for RANTES, 10 mg/kg for thioglycollate |
| Administration | Oral administration 30 or 15 minutes before injection of RANTES or thioglycollate |
| Molecular Weight | 285.22 |
| Formula | C11H5F2NO4S |
| CAS Number | 648449-76-7 |
| Solubility (25°C) | DMSO 47 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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