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Purity: ≥98%
AZD6482 (KIN193) is a novel, potent, selective and ATP competitive PI3Kβ (phosphatidylinositol-3-kinase) inhibitor with potential anticancer activity. In cell-free assays, it is 109-fold more selective against PI3Kβ than PI3Kδ, PI3Kα and PI3Kγ and inhibits p110β with an IC50 of 0.69 nM. According to reports, the p110β isoform of PI3K is necessary for the development of PTEN-null tumors. Therefore, the development of p110-selective inhibitors, such as AZD6482, is desirable for the treatment of cancer.
| Targets |
PI3Kα (IC50 = 136 nM); PI3Kβ (IC50 = 0.69 nM); PI3Kδ (IC50 = 13.6 nM); PI3Kγ (IC50 = 47.8 nM); PI3K-C2β (IC50 = 54.1 nM); hVps34 (IC50 = 3390 nM); DNA-PK (IC50 = 53.7 nM); PI4Kα (IC50 = PI4Kα nM); mTOR (IC50 = 3930 nM); Autophagy
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| ln Vitro |
An in vitrokinase assay demonstrates that AZD 6482 (KIN-193) is highly potent in the inhibition of p110β’s kinase activity (IC50 of 0.69 nM) and has 200, 20, and 70-fold selectivity over p110α, p110δ, and p110γ isoforms, respectively. AZD 6482 demonstrates a selectivity of 80 fold over PI3K-C2 and DNA-PK as well as a preference of more than 1,000 fold over other phosphatidylinositol-3 kinase-related kinases (PIKKs). The use of the KinomeScan method to profile AZD 6482's interactions with a panel of 433 kinases against those kinases shows that AZD 6482 interacts with PI3Ks with a high degree of specificity. To determine whether AZD 6482 selectively targets PTEN-deficient tumors, the effect of AZD 6482 is tested on cell proliferation on a large panel of 422 cancer cell lines using high-throughput tumor cell line profiling. AZD 6482 has an EC50<5 µM and is sensitive to 35% of cell lines with PTEN mutations (20 out of 57) and 16% of cell lines with wild-type PTEN (58 out of 365)[1].
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| ln Vivo |
The plasma concentration of AZD 6482 peaked at one hour after injection and dropped to undetectable levels by four hours. Both tumors driven by CA-p110α- and those not driven by CA-p110β- have AZD 6482 concentrations that are similar to plasma levels. The phosphorylation of AKT is significantly reduced at 1 hour after AZD 6482 injection in Rat1-CA-p110β tumors, but remains unchanged in Rat1-CAp110 tumors, according to analyses of tumor lysates harvested at different time points after the drug injection[1].
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| Enzyme Assay |
AZD 6482 (KIN-193) is profiled at a concentration of 10 µM against a diverse panel of 433 kinases. Scores for primary screen hits are expressed as a percentage of the DMSO control (% control). No quantifiable binding is found for kinases for which a score is not displayed. Scores of zero are considered strong hits because the lower the score, the lower the Kd is likely to be. Scores are not a precise indicator of affinity but are related to the likelihood of a hit. At a screening concentration of 10 µM, a score of less than 10% denotes that the false positive probability is less than 20% and that the Kd is most likely less than 1 µM. Although it is challenging to determine a quantitative affinity from a single-point primary screen, a score between 1 and 10% implies that the false positive probability is less than 10%. A score of less than 1% implies that the false positive probability is less than 5% and the Kd is most likely less than 1 µM[1].
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| Cell Assay |
Determined is cell viability. In a nutshell, cells are plated in 5% FBS medium at a density that ensures cell growth throughout drug treatment (about 15% for most cell lines). Drug treatment begins 24 hours after seeding and lasts for 72 hours. Syto60, a red fluorescent DNA stain, is used to fix and colorize cells. The relative fluorescence intensity from drug-treated wells over untreated wells, after background subtraction (cells-free wells), is used to calculate the relative cell number. In two-fold dilution steps, AZD 6482 (KIN-193) doses ranging from 5.12 µM to 0.02 µMare used in nine doses. Using a fixed top and bottom sigmoidal fitting algorithm implemented in PipelinePilot[1], the IC50, or 50% cell number compared to control (untreated) wells, is ascertained.
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| Animal Protocol |
Mice; Approximately 6-8 week-old female nude mice are injected s.c. with Rat1-Myr-HA-p110α(Rat1-CAp110α) cells (1×106cells in 40% matrigel) in one flank (site 1) and Rat1-Myr-HA-p110β (Rat1-CAp110β) cells (0.5×106cells in 10% matrigel) in the contralateral flank (site 2). When tumors reach a volume of 500 mm3 or less, mice are given AZD 6482, which is formulated in 7.5% NMP, 40% PEG400, and 52.5% dH2O, at a dose of 0.1 mL per kilogram of body weight. Blood samples are drawn directly from the heart, and tumors are collected at 0, 1, 4, 8, and 24 hours after the compound has been administered. At -80°C, separated serum is kept in storage. The DMPK group uses LC-MS/MS analysis to determine the drug concentrations in serum and tumor sample.
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| References | |
| Additional Infomation |
2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid is a pyridopyrimidine.
AZD-6482 is under investigation in clinical trial NCT00688714 (Study to Investigate Safety and Tolerability of a Single Dose of AZD6482). |
| Molecular Formula |
C22H24N4O4
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|---|---|
| Molecular Weight |
408.45036
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| Exact Mass |
408.179
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| Elemental Analysis |
C, 64.69; H, 5.92; N, 13.72; O, 15.67
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| CAS # |
1173900-33-8
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| Related CAS # |
(Rac)-AZD 6482;663620-70-0
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| PubChem CID |
44137675
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| Appearance |
white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
635.5±65.0 °C at 760 mmHg
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| Flash Point |
338.1±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.664
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| LogP |
4.07
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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 |
1
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| SMILES |
O=C1N2C(C([C@H](NC3=CC=CC=C3C(O)=O)C)=CC(C)=C2)=NC(N4CCOCC4)=C1
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| InChi Key |
IRTDIKMSKMREGO-OAHLLOKOSA-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)/t15-/m1/s1
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| Chemical Name |
2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid
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| Synonyms |
AZD-6482; AZD 6482; AZD6482
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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: ~82 mg/mL (~200.8 mM)
Water: <1 mg/mL Ethanol: ~10 mg/mL (~24.5 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. View More
Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5%Propylene glycol: 30 mg/mL |
| 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.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00853450 | Completed | Drug: AZD6482 Drug: Clopidogrel |
Antiplatelet Effect | AstraZeneca | February 2009 | Phase 1 |
| NCT00688714 | Completed | Drug: AZD6482 Drug: Placebo |
Antiplatelet Effect | AstraZeneca | January 2008 | Phase 1 |
Identification of KIN-193 (AZD6482) as a p110β specific inhibitor.Cancer Discov. 2012 May;2(5):425-33. |
In vivocharacterization of the anti-cancer potential of KIN-193.A,Pharmacokinetics and pharmocodynamics of KIN-193 in mice.Cancer Discov. 2012 May;2(5):425-33. |
In vivoeffect of KIN-193 on PTEN-deficient tumors.Cancer Discov. 2012 May;2(5):425-33. |
Effects of KIN-193 on PTEN-deficient cancer cells.Cancer Discov. 2012 May;2(5):425-33. |
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