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| Targets |
This compound targets phosphoinositide 3-kinase beta (PI3Kbeta/p110beta). It functions as a potent, selective, and ATP-competitive inhibitor of this kinase. In cell-free assays, AZD 6482 (the active enantiomer) exhibits IC50 values of 0.69 nM for PI3Kbeta, 13.6 nM for PI3Kdelta, 47.8 nM for PI3Kgamma, and 136 nM for PI3Kalpha, demonstrating approximately 20-fold, 70-fold, and 200-fold selectivity over PI3Kdelta, PI3Kgamma, and PI3Kalpha respectively. The compound's high selectivity for PI3Kbeta over other class I PI3K isoforms is a key feature of its pharmacological profile, making it a valuable tool for studying PI3Kbeta-specific biological functions and therapeutic applications.
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| ln Vitro |
In cell-free enzymatic assays, AZD 6482 demonstrates potent inhibition of PI3Kbeta with an IC50 of 0.69 nM. It shows significantly reduced activity against other PI3K isoforms, with IC50 values of 13.6 nM for PI3Kdelta, 47.8 nM for PI3Kgamma, and 136 nM for PI3Kalpha. The compound acts as an ATP-competitive inhibitor, binding to the ATP-binding pocket of the kinase. This selectivity profile has been characterized in multiple independent studies using purified enzyme preparations and standardized kinase activity assays. The compound's potent and selective inhibition of PI3Kbeta over other class I PI3K isoforms is a distinguishing feature of its in vitro activity profile. In vitro cellular studies have demonstrated that AZD 6482 effectively inhibits PI3Kbeta-dependent signaling pathways in various cell lines. The compound shows antiplatelet effects with a maximal effect achieved at 1 microM in in vitro tests. In PTEN-deficient tumor cell lines, AZD 6482 selectively inhibits cell growth, consistent with the role of PI3Kbeta in PTEN-loss driven cancers. The compound has been shown to attenuate platelet function through inhibition of PI3Kbeta-mediated signaling pathways, resulting in a mild and generalized antiplatelet effect that attenuates but does not completely inhibit multiple signaling pathways. These cellular activities support its potential as both an antithrombotic and anticancer agent.
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| ln Vivo |
In vivo studies have shown that AZD 6482 selectively inhibits the growth of PTEN-deficient tumor xenografts, including HCC70 and PC3 models. The compound exhibits antithrombotic activity in preclinical models, demonstrating efficacy in reducing thrombus formation. In dog models, AZD 6482 achieved a maximal anti-platelet effect at 1 microM in ex vivo tests. Oral administration of AZD 6482 has been studied in various in vivo models, including prostate cancer models, where it was administered orally to evaluate its effects on immune cell populations and tumor growth. The compound's in vivo efficacy supports its therapeutic potential in both thrombosis and oncology indications.
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| Enzyme Assay |
The in vitro enzyme/receptor binding assay for AZD 6482 typically involves measuring the inhibition of PI3K kinase activity using purified recombinant PI3K isoforms (alpha, beta, gamma, delta) in a kinase activity assay. The assay is performed in the presence of ATP and a phosphoinositide substrate, with compound added at varying concentrations to determine IC50 values. The reaction is initiated by the addition of ATP and terminated after a specified incubation period. The amount of phosphorylated product is quantified using a suitable detection method, such as a scintillation proximity assay or fluorescence-based detection. IC50 values are calculated by fitting the inhibition data to a sigmoidal dose-response curve.
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| Cell Assay |
In vitro cell-based assays for AZD 6482 typically utilize cell lines such as PTEN-deficient tumor cells (e.g., HCC70, PC3) to evaluate anti-proliferative effects. Cells are cultured in appropriate media and treated with varying concentrations of the compound for 48-72 hours. Cell viability is assessed using standard assays such as MTT, CCK-8, or ATP-based luminescence assays. For platelet function studies, human or animal platelets are isolated and treated with AZD 6482, followed by activation with agonists such as ADP or thrombin. Platelet aggregation is measured using aggregometry, and signaling pathway inhibition is assessed by Western blotting for phosphorylated AKT and other downstream effectors.
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| Animal Protocol |
In vivo animal studies for AZD 6482 are conducted in mouse and dog models. For antitumor efficacy, PTEN-deficient tumor xenografts (HCC70, PC3) are established in immunocompromised mice, and AZD 6482 is administered orally at various doses. Tumor volume is measured regularly to assess growth inhibition. For antithrombotic studies, appropriate thrombosis models are used in dogs or mice, with compound administered orally or intravenously. Blood samples are collected to measure platelet aggregation ex vivo. Pharmacodynamic markers such as phosphorylated AKT levels in platelets or tumor tissues are assessed to confirm target engagement.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of AZD 6482 have been characterized in preclinical species. The compound shows good oral bioavailability and can be formulated for oral administration. For in vivo formulations, AZD 6482 is soluble in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% saline at concentrations ≥ 2.5 mg/mL. The compound is also soluble in 10% DMSO + 90% corn oil at ≥ 2.5 mg/mL. In vitro solubility in DMSO is approximately 33.33 mg/mL (~81.60 mM). The compound shows rapid absorption following oral administration and demonstrates dose-proportional exposure in preclinical studies. Detailed half-life and clearance data are available in published pharmacokinetic studies.
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| Toxicity/Toxicokinetics |
Toxicology data for AZD 6482 from preclinical studies indicate a favorable safety profile. The compound was developed as an antithrombotic agent with a reduced bleeding risk compared to traditional therapies, suggesting an improved therapeutic index. In animal models, the compound demonstrates efficacy at doses that are well-tolerated without significant systemic toxicity. The compound's selectivity for PI3Kbeta over other PI3K isoforms is believed to contribute to its improved safety profile, as non-selective PI3K inhibitors are associated with greater toxicity. Detailed toxicological studies, including acute and repeat-dose toxicity assessments, have been conducted as part of the preclinical development program but specific LD50 values are not publicly available.
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| References | |
| Additional Infomation |
AZD 6482 was originally developed by AstraZeneca as a novel PI3Kbeta inhibitor for antithrombotic therapy. The compound has been evaluated in human target validation studies, demonstrating antiplatelet effects ex vivo in human samples. Its mechanism of action involves ATP-competitive inhibition of PI3Kbeta, leading to reduced AKT phosphorylation and downstream signaling. The compound has also been investigated for its potential in oncology, particularly in cancers with PTEN mutations where PI3Kbeta signaling is upregulated. As a research compound, AZD 6482 (and its racemate rac-AZD 6482) is widely used in academic and pharmaceutical research to study PI3Kbeta biology. The compound is not approved for clinical use and is available only for research purposes.
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| Molecular Formula |
C22H24N4O4
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| Molecular Weight |
408.45036
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| Exact Mass |
408.18
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| CAS # |
663620-70-0
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| Related CAS # |
AZD 6482;1173900-33-8
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| PubChem CID |
10364098
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| Appearance |
White to light yellow solid powder
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| LogP |
2.848
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
838
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CN2C(=O)C=C(N=C2C(=C1)C(C)NC3=CC=CC=C3C(=O)O)N4CCOCC4
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| InChi Key |
IRTDIKMSKMREGO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H24N4O4/c1-14-11-17(15(2)23-18-6-4-3-5-16(18)22(28)29)21-24-19(12-20(27)26(21)13-14)25-7-9-30-10-8-25/h3-6,11-13,15,23H,7-10H2,1-2H3,(H,28,29)
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| Chemical Name |
2-[1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethylamino]benzoic acid
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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 : ~33.33 mg/mL (~81.60 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 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 (6.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4483 mL | 12.2414 mL | 24.4828 mL | |
| 5 mM | 0.4897 mL | 2.4483 mL | 4.8966 mL | |
| 10 mM | 0.2448 mL | 1.2241 mL | 2.4483 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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