AZD6482

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:
Nylander S, Kull B, Björkman 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.

Human target validation of phosphoinositide 3-kinase (PI3K)beta: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kbeta inhibitor.[Pubmed:22906130]

J Thromb Haemost. 2012 Oct;10(10):2127-36.

BACKGROUND: Based on in vitro and animal data, PI3Kbeta is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. OBJECTIVE: To strengthen the PI3Kbeta target validation using the novel, short-acting inhibitor AZD6482. METHODS AND RESULTS: AZD6482 is a potent, selective and ATP competitive PI3Kbeta inhibitor (IC(50) 0.01 mum). A maximal anti-platelet effect was achieved at 1 mum in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC(50) of 4.4 mum). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 mum but reduced by about 60% at a plasma exposure of 27 mum. In man, the homeostasis model analysis (HOMA) index increased by about 10-20% at the highest plasma concentration of 5.3 mum. CONCLUSIONS: This is the first human target validation for PI3Kbeta inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at 'supratherapeutic' plasma concentrations may attenuate insulin signaling, most likely through PI3Kalpha inhibition.

Functional characterization of an isoform-selective inhibitor of PI3K-p110beta as a potential anticancer agent.[Pubmed:22588880]

Cancer Discov. 2012 May;2(5):425-33.

UNLABELLED: Genetic approaches have shown that the p110beta isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110beta-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collection of compounds possessing activities against kinases in the PI3K superfamily and identified a potent and selective p110beta inhibitor: KIN-193. We show that KIN-193 is efficacious specifically in blocking AKT signaling and tumor growth that are dependent on p110beta activation or PTEN loss. Broad profiling across a panel of 422 human tumor cell lines shows that the PTEN mutation status of cancer cells strongly correlates with their response to KIN-193. Together, our data provide the first pharmacologic evidence that PTEN-deficient tumors are dependent on p110beta in animals and suggest that KIN-193 can be pursued as a drug to treat tumors that are dependent on p110beta while sparing other PI3K isoforms. SIGNIFICANCE: We report the first functional characterization of a p110beta-selective inhibitor, KIN-193, that is efficacious as an antitumor agent in mice. We show that this class of inhibitor holds great promise as a pharmacologic agent that could be used to address the potential therapeutic benefit of treating p110beta-dependent PTEN-deficient human tumors.