AZD6482

Modify Date: 2024-01-02 14:03:46

AZD6482 Structure
AZD6482 structure
 Common Name AZD6482
CAS Number 1173900-33-8 Molecular Weight 408.450
Density 1.4±0.1 g/cm3 Boiling Point 635.5±65.0 °C at 760 mmHg
Molecular Formula C22H24N4O4 Melting Point N/A
MSDS N/A Flash Point 338.1±34.3 °C

 Use of AZD6482


AZD 6482 is a potent and selective p110β inhibitor with IC50 of 0.69 nM.

 Names

Name 2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid
Synonym More Synonyms

 AZD6482 Biological Activity

Description AZD 6482 is a potent and selective p110β inhibitor with IC50 of 0.69 nM.
Related Catalog
Target

PI3Kα:136 nM (IC50)

PI3Kβ:0.69 nM (IC50)

PI3Kδ:13.6 nM (IC50)

PI3Kγ:47.8 nM (IC50)

PI3K-C2β:54.1 nM (IC50)

hVps34:3390 nM (IC50)

DNA-PK:53.7 nM (IC50)

PI4Kα:8830 nM (IC50)

mTOR:3930 nM (IC50)

Autophagy

In 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 also exhibits selectivity of ~80 fold over PI3K-C2β and DNA-PK and more than 1,000-fold over other phosphatidylinositol-3 kinase–related kinases (PIKKs). An inhibitor-kinase interaction profiling of AZD 6482 against a panel of 433 kinases using the KinomeScan approach demonstrates that AZD 6482 is highly selective in its interaction with PI3Ks. 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. 35% of cell lines with PTEN mutations (20 out of 57) and 16% of cell lines with wild-type PTEN (58 out of 365) are sensitive to AZD 6482 with a threshold of EC50<5 µM[1].
In Vivo To determine the pharmacodynamics of AZD 6482 (KIN-193) in tumors in vivo, rat fibroblast (Rat1) cells are engineered to express both p53DD, a dominant negative mutant of p53, and a constitutively activated myr-p110β (Rat1-CA-p110β) to enable these cells to form xenograft tumors in mice. For comparison, an isogenic Rat1 cell line expressing p53DD and myr-p110α (Rat1-CA-p110α) is also generated. Rat1-CA-p110α and Rat1-CA-p110β cells are introduced subcutaneously into the contralateral flanks of athymic mice such that tumors driven by activated p110α or p110β would be exposed to identical conditions and that concern about animal-to-animal variability could be eliminated. When tumors reach a volume of ~500 mm3, the tumor-bearing mice receives a single IP injection of AZD 6482 (10 mg/kg). The plasma concentration of AZD 6482 is highest at 1 hour post-injection and declined to undetectable levels by 4h. Concentrations of AZD 6482 in both the CA-p110α- and CA-p110β-driven tumors parallel the plasma concentrations. Analyses of tumor lysates harvested at various time points after AZD 6482 injection reveal that the phosphorylation of AKT is significantly reduced at 1hour after AZD 6482 injection in Rat1-CA-p110β tumors, but remain unchanged in Rat1-CAp110α tumors[1].
Kinase 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 reported as percent of the DMSO control (% control). For kinases where no score is shown, no measurable binding is detected. The lower the score, the lower the Kd is likely to be, such that scores of zero represent strong hits. Scores are related to the probability of a hit, but are not strictly an affinity measurement. At a screening concentration of 10 µM, a score of less than 10% implies that the false positive probability is less than 20% and the Kd is most likely less than 1 µM. A score between 1-10% implies that the false positive probability is less than 10%, although it is difficult to assign a quantitative affinity from a single-point primary screen. 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].
Cell Assay Cell viability is determined. Briefly, cells are seeded in medium containing 5% FBS at a density insuring cell growth throughout drug treatment (~15% for most cell lines). Drug treatment is started 24 h post seeding and continued for 72 h. Cell are fixed and stained using Syto60, a red fluorescent DNA stain. The relative cell number is calculated by taking the ratio of the relative fluorescence intensity from drug treated wells over untreated wells after background subtraction (cells-free wells). Nine doses of AZD 6482 (KIN-193) are used in 2-fold dilution steps ranging from 5.12 µM to 0.02 µM. IC50, corresponding to 50% cell number compared to control (untreated) wells, is determined using a fixed top and bottom sigmoidal fitting algorithm implemented in PipelinePilot[1].
Animal Admin Mice[1] Approximately 6-8 week-old female nude mice are injected s.c. with Rat1-Myr-HA-p110α(Rat1-CAp110α) cells (1×106 cells in 40% matrigel) in one flank (site 1) and Rat1-Myr-HA-p110β (Rat1-CAp110β) cells (0.5×106 cells in 10% matrigel) in the contralateral flank (site 2). When tumors grow to ~500 mm3, mice are dosed once by ip injection with AZD 6482 formulated in 7.5% NMP, 40% PEG400, 52.5% dH2O at 0.1 mL/10g body weight and 10 mg/kg. Tumors are collected at 0, 1, 4, 8, and 24 h following compound administration and blood samples are obtained by direct heart puncture. Serum is separated and stored at -80°C. The drug concentrations in serum and tumor samples are assessed by LC-MS/MS analysis by the DMPK group.
References

[1]. Ni J, et al. Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. Cancer Discov. 2012 May;2(5):425-33.

 Chemical & Physical Properties

Density 1.4±0.1 g/cm3
Boiling Point 635.5±65.0 °C at 760 mmHg
Molecular Formula C22H24N4O4
Molecular Weight 408.450
Flash Point 338.1±34.3 °C
Exact Mass 408.179749
PSA 96.17000
LogP 4.07
Vapour Pressure 0.0±2.0 mmHg at 25°C
Index of Refraction 1.664

 Safety Information

Hazard Codes Xi
HS Code 2934999090

 Customs

HS Code 2934999090
Summary 2934999090. other heterocyclic compounds. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

 Synonyms

Benzoic acid, 2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl]ethyl]amino]-
PI3-kinase |A inhibitor,AZD6482
2-({(1R)-1-[7-Methyl-2-(4-morpholinyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl]ethyl}amino)benzoic acid
AZD6482
AZD 6482
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