A PI3Kβ inhibitor
AZD6428 is a potent, selective and ATP-competitive PI3Kβ inhibitor. IC50 are 0.69, 13.6, 47.8 and 136 nM for PI 3-Kβ, PI 3-Kδ, PI 3-Kγ and PI 3-Kα, respectively.
PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. It plays a key role in PI3K/Akt/mTOR pathway.
In vitro, AZD6482 inhibited insulin-activated uptake of human adpocyte glucose (IC50=4.4 μm). A full anti-thrombotic response with no increased bleeding or blood loss was observed in dog treated with AZD6482 in vivo. It also showed good tolerance in a three-hour AZD6482 infusion in healthy volunteers. There was an approx.10-20% rise at 5.3 μm (highest plasma concentration) according to the homeostasis model analysis index. [1]
Reference:
[1].Nylander S, Kull B, Bj?rkman JA et al.? Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost. 2012 Oct;10(10):2127-36.
| Cell experiment [1]: | |
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Cell lines |
Primary human insulin sensitive adipocytes |
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Preparation method |
The solubility of this compound in DMSO is >20.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.4-1 μM |
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Applications |
AZD6482 is a novel isoform-selective inhibitor of PI3Kβ (phosphoinositide 3-kinase) that blocks the interaction of the enzyme with ATP. AZD6482 concentration-dependently inhibited insulin-induced glucose uptake by human adipocytes. Taken together, AZD6482 inhibited platelet aggregation induced by low agonist concentrations. |
| Animal experiment [2]: | |
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Animal models |
Folts dog model |
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Dosage form |
intravenously (i.v.) over 30-min periods (bolus 0.03–1.3 μg kg-1) and (infusion 0.005–0.24 μg kg min-1) |
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Application |
In vivo in dog, AZD6482 induced a concentration-dependent anti-thrombotic effect in vivo in the dog [abolition of the CFRs(cyclic flow reductions)]. AZD6482 left the shear induced primary platelet aggregation intact but inhibits secondary platelet aggregation, produced a complete antithrombotic effect without significantly compromising hemostasis as no increase in bleeding time or blood loss was seen at plasma exposure that achieved a full anti-thrombotic effect. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Nylander S, Kull B, Bjrkman JA ., et al.Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost. 2012 Oct;10(10):2127-36. | |
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