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.
|Source||PLoS One (2016). Figure 6. AS-604850|
|Cell Lines||resazurin reduction assay|
|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 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.|
|Incubation time||2 - 4 hours|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 47 mg/mL|
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