AZD 6482

1173900-33-8

408.45

DMSO : >= 100 mg/mL (244.83 mM)

PI3K/Akt/mTOR; Autophagy

AZD 6482 (KIN-193) is a potent and selective p110beta inhibitor with an IC₅₀ of 0.69 nM. IC50 & Target: IC50: 0.69 nM (p110beta)^[1] In Vitro: An in vitrokinase assay demonstrates that AZD 6482 (KIN-193) is highly potent in the inhibition of p110beta's kinase activity (IC₅₀ of 0.69 nM) and has 200, 20, and 70-fold selectivity over p110alpha, p110delta, and p110gamma isoforms, respectively. AZD 6482 also exhibits selectivity of ca.80 fold over PI3K-C2beta 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 uM^[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-p110beta (Rat1-CA-p110beta) to enable these cells to form xenograft tumors in mice. For comparison, an isogenic Rat1 cell line expressing p53DD and myr-p110alpha (Rat1-CA-p110alpha) is also generated. Rat1-CA-p110alpha and Rat1-CA-p110beta cells are introduced subcutaneously into the contralateral flanks of athymic mice such that tumors driven by activated p110alpha or p110beta would be exposed to identical conditions and that concern about animal-to-animal variability could be eliminated. When tumors reach a volume of ca.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-p110alpha- and CA-p110beta-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-p110beta tumors, but remain unchanged in Rat1-CAp110alpha tumors^[1].