AS-605240 648450-29-7

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Molecular Weight: 257.27 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, respectively.






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 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.

In vitro PI3K lipid 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:


[1]

Cell lines	RAW264 macrophages
Concentrations	1 nM - 10 μM, dissolved in DMSO
Incubation Time	30 min
Method	After a 3-hour starvation in serum-free medium, Cells 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.

Animal Study:


[1]

Animal Models	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	Dissolved in 0.5% carboxymethylcellulose/0.25% Tween-20
Dosages	50 mg/kg
Administration	Orally
Solubility	0.5% CMC/0.25% Tween 80, 11 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	257.27
Formula	C12H7N3O2S
CAS No.	648450-29-7

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	0.4 mg/mL (1.55 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	0.5% CMC/0.25% Tween 80	11 mg/mL
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	(Z)-5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione

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Product Categories : PI3K/Akt/mTOR > PI3K Inhibitor