Phosphatidylinositol 3-kinase (PI3K) catalyzes the phosphorylation of the 3' hydroxyl position of PIs to produce the second messengers PtdIns-(3,4)-P2 and PtdIns-(3,4,5)-P3. PI3Kα, β, and δ are class 1A enzymes composed of p110 and p85 subunits, whereas PI3Kγ is a class 1B PI3K composed of a p110 catalytic subunit and a p101 or p84 regulatory subunit. AZD6482 is a PI3K inhibitor that targets the β isoform more potently than PI3Kδ, PI3Kγ, or PI3Kα (IC50s = 0.69, 13.6, 47.8, and 136 nM, respectively). It displays 80-fold selectivity for PI3Kβ over PI3k-C2 and DNA-PK and more than 1,000-fold over other PI3K-related kinases. AZD6482 blocks Akt signaling and tumor growth in a large number of cancer cell lines, including those that are dependent on PI3Kβ activation or PTEN loss. AZD6482 (20 mg/kg, i.p.) suppresses the growth of PTEN-deficient xenograft tumors in mice. It also produces an anti-thrombotic effect in dogs without an increase in bleeding time or blood loss.
