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Purity: ≥98%
AS-605240 is a novel, potent, orally bioactive andATP-competitiveinhibitor of PI3-kinase γ (PI3Kγ) with potential anti-inflammatory activity. With an IC50 of 8 nM, it selectively inhibits PI3Kγ and, in cell-free assays, is >30-fold and 7.5-fold more selective for PI3Kγ than PI3Kδ/β and PI3Kα, respectively. Inflammatory illnesses may be treated with AS605240. According to studies, taking AS605240 orally significantly reduced collagen buildup and prevented lung inflammation.
| Targets |
Phosphoinositide 3-kinase gamma (PI3Kγ) (IC₅₀ = 8 nM) [1]
PI3Kγ (IC50 = 8 nM); PI3Kδ (IC50 = 60 nM); >30-fold selectivity over PI3Kα/β [1][3] PI3Kα (IC50 = 60 nM); PI3Kβ (IC50 = 270 nM); PI3Kδ (IC50 = 300 nM); PI3Kγ (IC50 = 8 nM); PI3Kγ (Ki = 7.8 nM); Autophagy |
|---|---|
| ln Vitro |
AS-605240 selectively inhibited PI3Kγ activity (IC₅₀ = 8 nM) with >30-fold selectivity over PI3Kα, PI3Kβ, and PI3Kδ isoforms. It suppressed fMLP-induced neutrophil chemotaxis and respiratory burst in primary murine neutrophils at 0.1–1 μM. [1]
In B cells, AS-605240 (1 μM) blocked CXCL13-induced Akt phosphorylation and impaired B cell migration in transwell assays. [2] AS-605240 (0.5–5 μM) inhibited LPS-induced TNF-α and IL-6 production in macrophages by suppressing NF-κB activation. [3] 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. [1] At SC-CA1 synapses in mice, AS-605240 (100 nM) eliminates NMDAR LTD, without affecting mGluR LTD, depotentiation, and LTP. [2] With an IC50 of 90 nM, AS-605240 blocks PKB phosphorylation caused by C5a. AS-605240 (1 M) prevents MCP-1 or CSF-1 from inducing PKB phosphorylation in bone marrow-derived monocytes (BMDMs). [1] When used at mice's SC-CA1 synapses, AS-605240 (100 nM) completely eliminates NMDAR LTD while having no effect on mGluR LTD, depotentiation, or LTP. [2] |
| ln Vivo |
Oral administration of AS-605240 (5 mg/kg/day) reduced joint inflammation, cartilage destruction, and bone erosion in the collagen-induced arthritis (CIA) mouse model by inhibiting neutrophil and macrophage infiltration. [1]
In the MRL/lpr mouse model of systemic lupus erythematosus (SLE), AS-605240 (100 mg/kg/day, oral) decreased autoantibody production, reduced splenic germinal center formation, and ameliorated kidney pathology. [2] AS-605240 (20 mg/kg, oral) attenuated zymosan-induced peritonitis in mice by reducing neutrophil recruitment (by 70%) and pro-inflammatory cytokine levels in peritoneal fluid. [3] 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. AS-605240 (50 mg/kg) also reduces joint inflammation and damage in a mouse model of collagen-induced arthritis. [1] AS-605240 (10 mg/kg) significantly improves insulin sensitivity and glucose tolerance in an obesity-induced diabetes model (ob/ob mice) without changing body weight. It also significantly lowers blood glucose levels. With a little less weight gain, AS-605240 (30 mg/kg) exhibits more significant effects. Additionally, AS-605240 lowers both the MCP-1 circulation levels and the abundance of ATMs. [3] |
| Enzyme Assay |
PI3Kγ kinase activity was measured using a radiometric assay. Recombinant PI3Kγ was incubated with phosphatidylinositol substrate and [γ-³²P]ATP. AS-605240 was added to determine IC₅₀ values. Selectivity was tested against other PI3K isoforms. [1]
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[33P]ATP, final concentrations) and lipid vesicles containing 18 M PtdIns and 250 M of PtdSer (final concentrations), in the presence of inhibitors or DMSO. By adding 250 g of Neomycin-coated Scintillation Proximity Assay (SPA) bead, the kinase reaction is stopped, and the process is then continued. |
| Cell Assay |
Neutrophil chemotaxis: Mouse neutrophils were placed in transwell chambers with fMLP as chemoattractant. AS-605240 pre-treatment (30 min) inhibited migration, quantified by cell counting. [1]
B cell migration: Splenic B cells were stimulated with CXCL13 in transwell plates. Migrated cells were counted after 3h; inhibition by AS-605240 was assessed via flow cytometry. [2] Macrophage cytokine assay: Peritoneal macrophages were stimulated with LPS ± AS-605240. TNF-α/IL-6 in supernatants were measured by ELISA; NF-κB activation was analyzed by EMSA. [3] A total of 5×105 BDC2.5 splenocytes and 50 μg/mL BDC2.5-peptide are incubated in vitro in a 96-well round-bottom plate for 48 h. The next step is to measure cell proliferation by pulse-dosing the cultures with 1 μCi of tritiated thymidine [3H]. |
| Animal Protocol |
Collagen-induced arthritis: DBA/1 mice received oral AS-605240 (5 mg/kg/day) in 0.5% methylcellulose daily after arthritis onset. Paw swelling and histopathology were monitored. [1]
SLE model: MRL/lpr mice were treated orally with AS-605240 (100 mg/kg/day) in methylcellulose from age 8–20 weeks. Autoantibodies and kidney histology were analyzed. [2] Peritonitis model: Mice were orally administered AS-605240 (20 mg/kg) in methylcellulose 1h before zymosan injection. Peritoneal lavage was collected 4h later for neutrophil counts and cytokine assays. [3] In this study, rats are bred for one week to affirm body weight and then randomLy divided into four experimental groups: (a) control group (rats are given vehicle only); (b) BLM group (rats are induced with BLM); (c) BLM + 25 mg/kg AS605240 group (rats are induced with BLM and then administrated with 25 mg/kg AS605240); (d) BLM + 50 mg/kg AS605240 group (the same protocol as the former group except a different dose of 50 mg/kg AS605240). Additionally, five rats are given 50 mg/kg of AS605240 to see if it has any side effects at the same time as the other four groups. Rats in groups (c), (d), and those receiving only AS605240 are given 25, 50, and 50 mg/kg of the drug orally by gavage, whereas rats in groups (control) and BLM are given only equivalence saline on day 1 (the day rats are given BLM is marked as day 0). For 28 days, the same dosage is administered once daily. |
| References | |
| Additional Infomation |
AS-605240 is a potent and selective PI3Kγ inhibitor that blocks leukocyte migration and activation, making it effective in autoimmune/inflammatory diseases. [1]
By inhibiting PI3Kγ in B cells, AS-605240 disrupts germinal center formation and autoantibody production, highlighting its therapeutic potential in SLE. [2] The suppression of NF-κB and cytokine production in macrophages by AS-605240 provides a mechanism for its anti-inflammatory effects in innate immunity. [3] First selective PI3Kγ inhibitor demonstrating therapeutic potential in both inflammatory and neurodegenerative diseases [1][2]. (5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione is a quinoxaline derivative that is quinoxaline in which the hydrogen at position 6 is replaced by a (2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl group. It is a potent inhibitor of the PI3Kgamma, with an IC50 of 8 nM and inhibits the progression of joint inflammation and damage in both lymphocyte-independent and dependent mouse models of rheumatoid arthritis. It has a role as an EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor, an anti-inflammatory agent and an antirheumatic drug. It is a quinoxaline derivative and a member of thiazolidinediones. |
| Molecular Formula |
C12H7N3O2S
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|---|---|
| Molecular Weight |
257.2679
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| Exact Mass |
257.025
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| Elemental Analysis |
C, 56.02; H, 2.74; N, 16.33; O, 12.44; S, 12.46
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| CAS # |
648450-29-7
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| Related CAS # |
648450-29-7
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| PubChem CID |
5289247
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| Appearance |
Pink to orange solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.792
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| LogP |
0.52
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
18
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| Complexity |
410
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(N([H])C(/C/1=C(\[H])/C1C([H])=C([H])C2C(C=1[H])=NC([H])=C([H])N=2)=O)=O
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| InChi Key |
SQWZFLMPDUSYGV-UXBLZVDNSA-N
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| InChi Code |
InChI=1S/C12H7N3O2S/c16-11-10(18-12(17)15-11)6-7-1-2-8-9(5-7)14-4-3-13-8/h1-6H,(H,15,16,17)/b10-6-
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| Chemical Name |
(5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione
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| Synonyms |
AS 605240; AS605240; AS-605,240; 648450-29-7; 8GRW063UT7; (E)-5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione; 5-(quinoxalin-6-ylmethylene)thiazolidine-2,4-dione; AS605,240; 2,4-Thiazolidinedione, 5-(6-quinoxalinylmethylene)-; 633-205-4; AS-605240
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~0.4 mg/mL (~1.6 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (9.72 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.72 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 0.5% CMC+0.25%Tween 80: 11mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8870 mL | 19.4348 mL | 38.8697 mL | |
| 5 mM | 0.7774 mL | 3.8870 mL | 7.7739 mL | |
| 10 mM | 0.3887 mL | 1.9435 mL | 3.8870 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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