Term on the right flank with 5106 U87MG, SK OV 3 or HCT 116 cells seeded in PBS. Tumor diameter example of the electronic caliper was measured using to the tumor to be calculated on the basis of the formula Gefitinib Iressa v 6. A66 was administered in 20% 2 hydroxypropyl cyclodextrin in water, was w Administered during BEZ 235 in 10% ethanol. Mice control-M The vehicle alone was administered dose A66. The drugs were anesthetized by intraperitoneal injection as free base corresponds to a dose of 10 ml kg K Determined body weight.

For tumor pharmacodynamic studies Mice again U is a single dose of A66 or vehicle inspected When the tumors reached approximately 8 mm in diameter. The animals were get 1 or 6 h after administration Tet and the tumors were removed and analyzed for protein concentration biopulverized.
For antitumor efficacy studies dosage began at tumors were well established, on average, about 7 mm in diameter. The cans were once t Resembled or twice t Separated resembled with injections of a minimum of about 8 h. Various schemes have been for all three xenograft models at the rate of tumor growth and tolerance of K Mice rpergewichts of control aids, Is used. The animals were t Dosed for 21 days or twice was like t Was like for 16 days, t Was like for 14 days and t Possible for 7 days. The animals were t Possible for signs of toxicity t threshold and the K Body weight was monitored recorded. The Mice were get Tet when they have developed mild signs of toxicity T or weight loss over 20% of initial weight.
TGI control calculated on the last day of dosing for the determination of tumor size E mice compared to M, The drug as a percentage of the tumor size E in comparison to M Average mice. The statistical significance of the TGI values were determined by ANOVA one-way analysis with Bonferroni multiple comparisons using GraphPad Prism fifth 02. Specific inhibitor RESULTS rst A66 characterized and best Firmed that it is a potent inhibitor of the type and oncogenic forms of thewild was p110, but not the table of the other class 1 drugs for the IC50 against various isoforms of PI3K assay using HTRF indicated IC 50 values are in nM. ND = not determined. PI3K isoform-A66, A66 SR 75 SN34452 PIK TGX 221 IC87114 p110 32 5000 1560 6 1000 1000 p110 E545K ND 24 30 540 1000 1000 p110 H1047R 43 ND 550 4th P110 7 1000 1000 12 500 12 500 25 000 80 12 1250 p110 1250 12 500 1000 164 130 41 ND 33 p110 3480 4350 1250 1250 Table 2 IC 50 against PI3K related kinases the form S A66 with or without the group carboximide IC50 are in nM.
ND = not determined. A66 S SN34452 kinase PI3K-C2 5000 10,000,462 6500 PI3K-C2, PI3K class III ND 5000 ND 5000 ND 5000 mTOR DNA-PK PI4K 5000 10,000,236,478 I PI4K isoforms of PI3K. We found a gr A66 Degree of selectivity eren t for p110 that PIK 75th In view of the r The big e class II PI3Ks, class III PI3K and PI4Ks in growth factor signaling, we have the activity T this and A66 in the direction of finding some limited cross-reactivity T with evaluated PI3K class II PI3K-C2 PI4K and PI4K isoform . Therewas no inhibition of lipid kinases or other kinases DNA-PK and mTOR linked. We also tested the inhibitory effects of 10 M A66 effects on two large panels of protein kinases e 110 and 318 kinases. This show, A66 is a very specific inhibitor of P110 , w While PIK-75, described earlier, the connection