| GDC-0941 is a novel small-molecule inhibitor of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ with IC50 of 3, 33, 3 and 75 nM, respectively. 1 μM GDC-0941 inhibits the human tyrosine kinase Flt3 and the human tyrosine kinase (TrkA) by 59 and 61%, respectively. GDC-0941 potently inhibits the phosphorylation of Akt in PC3-NCI (prostate) and MCF7.1 cells (breast), with IC50 values ranging from 28 to 37 nM. GDC-0941 is also able to inhibit the proliferation of MCF7.1 and PC3-NCI cells with IC50 values of 0.72 and 0.28 μM, respectively.[1] GDC-0941 inhibits mammalian target of rapamycin (mTOR) and DNA-depended protein kinase (DNA-PK) with IC50 values of 0.58 and 1.23 μM, respectively. The cellular GI50 values of GDC-0941 are 0.95, 0.28, 0.54, 0.07, 0.15 and 0.12 μM in human cancer cell lines U87MG, PC3, SKOV-3, IGROV-1, Detroit 562 and human umbilical vein endothelial cell (HUVEC), respectively. GDC-0941 exhibits more potent antiproliferative activity against IGROV-1 ovarian cancer cells compared with U87MG glioblastoma cells. The IC50 values of GDC-0941 for the inhibition of phosphorylation of Ser473 on AKT in IGROV-1 cells following 2- or 8-hour exposure are 18 and 38 nM, respectively. In three human colon cancer cell lines (LoVo, SNUC2B and HCT116), the antiproliferative GI50 values of GDC-0941 range 9-fold from 180 nM (for LoVo) to 1,627 nM (for SNUC2B), whereas the IC50 values for inhibition of AKT phosphorylation on Ser473 following 2-hour treatment again range only 2-fold from 14 nM (for HCT116) to 33 nM (for SNUC2B). In U87MG glioblastoma xenografts, GDC-0941 (50 mg/kg or 150 mg/kg) significantly reduces the levels of AKT phosphorylation (at both Thr308 and Ser473 sites) and inhibition is maintained for the 8-hour observation period, especially at the 150 mg/kg dose. GDC-0941 significantly inhibits downstream in the phosphatidylinositide 3-kinase pathway, phosphorylation of GSK3β and P70S6K. The mean tumor volumes of GDC-0941 treated (50, 100 and 150 mg/kg) at day 19 are below the original volumes. Values of the percentage treated/control (T/C) based on final tumor weights range from 23.4% (76.6% inhibition) at 25 mg/kg GDC-0941 to 2.3% (97.7% inhibition) at 150 mg/kg GDC-0941. In IGROV-1 ovarian carcinoma xenografts, the T/C values decrease from 50.5% (49.5% inhibition) at 25 mg/kg GDC-0941 to 19.7% (80.3% inhibition) at 150 mg/kg GDC-0941.[2] |
