product name AS-605240
Description: AS-605240 selectively inhibits PI3Kγ with IC50 of 8 nM, over 30-fold and 7.5-fold more selective for PI3Kγ than PI3Kδ/β and PI3Kα in cell-free assays, respectively. AS605240 has been proved effective on several inflammatory diseases. Orally administration of AS605240 significantly prevented lung inflammation and reduced collagen deposition. AS605240 also inhibited augmented expression of TNF-alpha and IL-1beta induced by bleomycin instillation. AS605240 may be a useful in treating inflammation diseases. AS605240 may represent a promising novel agent for the future therapy of pulmonary fibrosis.
References: Nat Med. 2005 Sep;11(9):936-43; Biochim Biophys Acta. 2008 Jan;1784(1):159-85.
257.27
Formula
C12H7N3O2S
CAS No.
648450-29-7
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 0.4 mg/mL (1.55 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
0.5% CMC+0.25% Tween 80: 11 mg/mL
Chemical Name
(Z)-5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione
other peoduct :
| In Vitro |
Kinase Assay: (1) For PI3Kγ: 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 μM ATP/100 nCi γ[33P]ATP, final concentrations) and lipid vesicles containing 18 μM PtdIns and 250 μM of PtdSer (final concentrations), in the presence of AS-605240 or DMSO. Kinase reaction is stopped by adding 250 μg of Neomycin-coated Scintillation Proximity Assay (SPA) beads. (2) For PI3Kα, β, and δ: varying amounts of ATP are incubated with the different purified PI3K isoforms and saturating concentrations of PtdIns. Consequently, IC50 determinations with PI3Kα, β, and δ, to evaluate inhibitor selectivity are performed as follows: 60 ng of PI3Kα are incubated at RT with kinase buffer, as described for PI3Kγ (but containing 89 μM ATP/300 nCi γ[33P]ATP and no Na Cholate, instead) and lipid vesicles containing 212 μM PtdIns and 58 μM of PtdSer. 100 ng of PI3Kβ are incubated at RT with kinase buffer (containing 70 μM ATP/300 nCi γ[33P]ATP, 4 mM MgCl2 and no Na Cholate) and lipid vesicles containing 225 μM PtdIns and 45 μM of PtdSer. 90 ng of PI3Kδ are incubated with kinase buffer (containing 65 μM ATP/300 nCi γ[33P]ATP, 1 mM MgCl2, and no Na Cholate) and lipid vesicles containing 100 μM PtdIns and 170 μM of PtdSer. The reactions are stopped after 2 hours. Cell Assay: After a 3-hour starvation in serum-free medium, Cells (RAW264 macrophages) are pretreated with AS-605240 or DMSO for 30 min and stimulated for 5 min with 50 nM of C5a. PKB phosphorylation is monitored using phosphorylated Ser473 Akt-specific antibody and standard ELISA protocols. AS-605240 is an ATP-competitive PI3Kγ inhibitor, with Ki values of 7.8 nM. AS-605240 is isoform-selective, for AS-605240 also inhibits PI3Kα, β, and δ, with IC50 of 60, 270, and 300 nM, respectively. AS-605240 inhibits C5a-mediated PKB phosphorylation with IC50 of 90 nM. In bone marrow-derived monocytes (BMDMs), AS-605240 (1 μM) blocks MCP-1- or CSF-1-induced PKB phosphorylation. At SC-CA1 synapses in mice, AS-605240 (100 nM) eliminates NMDAR LTD, without affecting mGluR LTD, depotentiation, and LTP. |
|---|---|
| In Vivo | In RANTES-induced mouse model of peritonitis, AS-605240 reduces neutrophil chemotaxis with ED50 of 9.1 mg/kg. In a αCII-induced arthritis, AS-605240 (50 mg/kg) protects against αCII-IA symptom. In a mouse model of collagen-induced arthritis, AS-605240 (50 mg/kg) also suppresses joint inflammation and damage. In an obesity-induced diabetes model (ob/ob mice), AS-605240 (10 mg/kg) lowers blood glucose levels, significantly improves both insulin sensitivity and glucose tolerance without affecting body weight. AS-605240 (30 mg/kg) displays more profound effects with slightly less weight gain. Moreover, AS-605240 reduces the abundance of ATMs and the circulating levels of MCP-1. |
| Animal model | RANTES-induced mouse model of peritonitis (female Balb/C or C3H), αCII-induced mouse model of arthritis, and collagen-induced mouse model of arthritis (CIA) (male DBA/1) |
| Formulation & Dosage | Dissolved in 0.5% carboxymethylcellulose/0.25% Tween-20; 50mg/kg; Oral gavage |
| References | [1] Camps M, et al. Nat Med, 2005, 11(9), 936-943.; [2] Kim JI, et al. Nat Neurosci, 2011, 14(11), 1447-1454. |
