AS252424

• Catalog No.: S2671
• CAS Number: 900515-16-4
• M. F.: C14H8FNO4S
• M. W.: 305.2810232
• Storage: -20°C

SYNONYMS

• IUPAC name: (5Z)-5-{[5-(4-fluoro-2-hydroxyphenyl)furan-2-yl]methylidene}-1,3-thiazolidine-2,4-dione
• IUPAC Traditional name: (5Z)-5-{[5-(4-fluoro-2-hydroxyphenyl)furan-2-yl]methylidene}-1,3-thiazolidine-2,4-dione

DATABASE IDS

• CAS Number: 900515-16-4

PROPERTIES

• Target: PI3K
• Salt Data: Free Base
• Storage Condition: -20°C

DETAILS

Description (English)

Biological Activity

• Description: AS-252424 is a novel, potent and selective inhibitor of PI3Kγ with IC50 of 33 nM.
• Targets: PI3Kγ; CK2 (casein kinase 2); PI3Kα
• IC50: 33 nM; 20 nM; 935 nM ^[1]
• In Vitro: AS-252424 is a furan-2-ylmethylene thiazolidinedione as a selective ATP-competitive PI3Kγ inhibitor with IC50 with 33 nM. AS-252424 shows reduced potency on PI3Kα with an IC50 with 935 nM. When screening against 80 different Ser/Thr and Tyr kinases, AS-252424 doesn’t show significant inhibit towards any of them at 10 μM except for CK2. AS-252424 inhibits C5a-mediated PKB/Akt phosphorylation in a concentration- dependent manner with submicromolar or low-micromolarIC50 value. AS-252424 inhibits MCP-1-mediated chemotaxis in wild-type primary monocytes in a concentration-dependent manner with an IC50 value of 52 μM, as well as in the monocytic cell line THP-1 with an IC50 value of 53 μM. ^[1] AS252424 specifically blocks proliferation in the pancreatic cancer cell lines HPAF and Capan1, as assessed by cell counting. ^[2] A recent research indicates 100 nM of AS-252424 significantly reduces [Ca^2+]i, I_Ca and Ca^2+ transients in HL-1 cardiomyocytes. ^[3]
• In Vivo: Oral administration of AS-252424 at 10 mg/kg results in moderate reduction of neutrophil recruitment (35%), almost matching the result observed in PI3Kγ-deficient mice. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro PI3Kγ Kinase Assay: Human PI3Kγ (100 ng) is incubated at RT with kinase buffer (10 mM MgCl₂, 1 mM β-glycerophosphate, 1 mM DTT, 0.1 mM Na₃VO₄, 0.1% Na Cholate and 15 M ATP/100 nCi γ[^33]ATP, final concentrations) and lipid vesicles containing 18 M PtdIns and 250 M of PtdSer (final concentrations), in the presence of AS-252424 or DMSO. Kinase reaction is stopped by adding 250 g of Neomycin-coated Scintillation Proximity Assay (SPA) beads and preceded.
• Protocol: Cell Assay ^[1]
• Cell Lines: Raw-264 macrophage
• Concentrations: 0.01 nM to 0.1 μM
• Incubation Time: 5 minutes
• Methods: After 3 hours of starvation in serum-free medium, Raw-264 macrophages are pretreated with AS-252424 or DMSO for 30 minutes and stimulated for 5 minutes with 50 nM C5a. PKB/Akt phosphorylation is monitored using phospho-Ser-473 Akt specific antibody and standard ELISA protocols.
• Protocol: Animal Study ^[1]
• Animal Models: Intraperitoneally injecting female C3H mice with thioglycollate (40 ml/kg) to induced a peritonitis mouse model
• Formulation: AS-252424 is dissolved in vehicle (0.5% carboxymethylcellulose/0.25% Tween-20) and adjusted the solution to 10 mL/kg of body weight.
• Doses: 10 mg/kg
• Administration: Oral administration 15 minutes before injection of thioglycollate

References

• References: [1] Pomel V, et al, J Med Chem, 2006, 49(13), 3857-3871.
• References: [2] Edling CE, et al, Clin Cancer Res, 2010, 16(20), 4928-4937.
• References: [3] Graves BM, et al, J Biomed Sci, 2012, 19(1), 59 [Epub ahead of print]

REFERENCES

• Pomel V, et al, J Med Chem, 2006, 49(13), 3857-3871.
• Edling CE, et al, Clin Cancer Res, 2010, 16(20), 4928-4937.
• Graves BM, et al, J Biomed Sci, 2012, 19(1), 59 [Epub ahead of print]