Omipalisib

A highly potent dual inhibitor PI3K/mTOR inhibitor with app Ki of 19/130/24/60/180/300 nM for p110α/p110β/p110γ/p110δ/mTORC1/mTORC2 respectively; shows equivalent activity for p110α mutants E542K/E545K/H1047R with Ki of 8/8/9 nM; inhibits pAKT-S473 in T47D cells (IC50=0.41 nM), also inhibits phosphorylation of AKTT308 and p70S6K; active in vivo and orally bioavailable.Solid Tumors Phase 1 Clinical (In Vitro) :Omipalisib (GSK2126458) potently inhibits the activity of common activating mutants of p110α (E542K, E545K, and H1047R) found in human cancer with Ki of 8 pM, 8 pM and 9 pM, respectively. Omipalisib causes a significant reduction in the levels of pAkt-S473 with remarkable potency in T47D and BT474 cells with IC50 of 0.41 nM and 0.18 nM, respectively. Furthermore, Omipalisib (GSK2126458) leads to a G1 cell cycle arrest and produces the inhibitory effect on cell proliferation in a large panel of cell lines, including T47D and BT474 breast cancer lines with IC50 of 3 nM and 2.4 nM, respectively. The combination of Omipalisib or GSK1120212 with Omipalisib enhances cell growth inhibition and decreases S6 ribosomal protein phosphorylation in drug-resistant clones from the A375 BRAF (V600E) and the YUSIT1 BRAF (V600K) melanoma cell lines. Omipalisib (GSK2126458) potentiates the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. (In Vivo) :In a BT474 human tumor xenograft model, Omipalisib (GSK2126458) treatment results in a dose-dependent reduction in pAkt-S473 levels, and exhibits dose-dependent tumor growth inhibition at a low dose of 300 μg/kg. Besides, Omipalisib (GSK2126458) shows low blood clearance and good oral bioavailability in four preclinical species (mouse, rat, dog, and monkey) .