Biological Activity
GDC-0941 (Pictilisib) is a potent inhibitor of PI3Kα/δ with an IC50 of 3 nM, with modest selectivity against p110β (11-fold) and p110γ (25-fold).
In Vitro
GDC-0941 and docetaxel reduce tumor cell viability by 80% or greater in the breast cancer cell lines than single-agent treatment. GDC-0941 inhibits Akt phosphorylation and downstream targets of Akt signaling such as pPRAS40 and pS6 in Hs578T1.2 (PI3Kα wild-type), MCF7-neo/HER2 (PI3Kα-mutant), and MX-1 (PTEN-null) tumor models. GDC-0941 decreases the time of docetaxel-induced mitotic arrest prior to apoptosis[1]. GDC-0941 shows a high efficacy of antitumor activity in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. GDC-0941 is highly efficacious in combination with U0126 in inducing cell growth inhibition, G0-G1 arrest and cell apoptosis. H460 cells with activating mutations of PIK3CA are relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA[3]. GDC-0941 reduces PI3K pathway activity in both cell lines, illustrated by decreased pAK. GDC-0941 significantly reduces secreted VEGF detected in the medium after hypoxic/anoxic exposure in all cells[4].
In Vivo
GDC-0941 (150 mg/kg, p.o.) leads to tumor stasis in MCF7-neo/HER2-bearing animals model. GDC-0941 and docetaxel result in tumor regressions during the treatment period leading to enhanced antitumor responses[1]. Tumours in the GDC-0941-treated mice show a marked non-linear shrinkage, and when the GDC-0941 treatment ceased, the tumours in the test cohort mice grow again[2]. GDC-0941 (25 or 50 mg/kg) reduces tumor growth and PI3K and HIF-1 pathway activity in eGFP-FTC133 tumor-bearing mice[4].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
