AKT is the central node of PI3K/AKT/mTOR pathway. The PH domain and ATP-competitive site are the main target site for research of new compound[1]. GDC-0068 (Ipatasertib) is an ATP-competitive pan Akt inhibitor with IC50 values of 5 nM, 18 nM and 8 nM on AKT 1, 2 and 3 isoforms, respectively[2]. Treatment of GDC-0068 on concentration of 0.1 - 25 μM caused decreased phosphorylation of the downstream targets of AKT, such as FoxO1 and FoxO3a, 4EBP1 and S6 in a dose- and time-dependent manner in PC-3, BT474M1, and IGROV-1 cell lines, accompanied by feedback increase in AKT phosphorylation. Treatment of GDC-0068 on concentration of 1 – 10 μM can induce G1-arrest (including in PC-3 cells) and increase in apoptotic and necrotic populations in a dose- and time-dependent manner in BT474M1 and MCF7-neo/HER2 cells, but not in PC-3 cells. In growth inhibition assay, cell lines with high Akt activity show more sensitivity to GDC-0068. GDC-0068 showed good pharmacokinetics and pharmacodynamics in xenograft models. The level of pPRAS40-T246 in LNCaP tumors at 1 and 4 hours after a single dose of GDC-0068 at 12.5, 25, 50, or 100 mg/kg decreased in a dose-dependent manner. GDC-0068 on dose of 50 mg/kg in combination with docetaxel induced tumor regression and stasis in the PC-3 and MCF7-neo/HER2 xenograft models[3]. The clinical trials of GDC-0068, including a completed phase 2 study of combination with paclitaxel as neoadjuvant treatment for participants with early stage triple negative breast cancer, have been done (see in https://clinicaltrials.gov/).
作用机制
GDC-0068 is an ATP-competitive AKT inhibitor.
Ipatasertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MOLM-13
75nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, results showed increased AKT phosphorylation.
Nat Cancer. 2022 Jul;3(7):837-851.
OCI-AML2
200nM
24 h
To validate selinexor’s ability to activate PI3K/AKT signaling, results showed increased AKT phosphorylation.
Nat Cancer. 2022 Jul;3(7):837-851.
PC3 cells
500 nM
Inhibited translation of HGF, SPP1, and BGN
Nat Cancer. 2023 Aug;4(8):1102-1121.
Pten-sh TC1 cells
500 nM
Inhibited translation of HGF, SPP1, and BGN
Nat Cancer. 2023 Aug;4(8):1102-1121.
BS-004
0.25–10 μM
72 h
GDC-0068 showed only a minor reduction in cell viability in the PIK3CA-wildtype cell line BS-004.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
MDA-MB-231 BrM2
0.25–10 μM
72 h
GDC-0068 showed only a minor reduction in cell viability in the PIK3CA-wildtype cell line MDA-MB-231 BrM2.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
JIMT-1 BR-3
0.25–10 μM
72 h
GDC-0068 showed modest reduction in cell viability in the PIK3CA-mutant cell line JIMT-1 BR-3.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
MDA-MB-453
0.25–10 μM
72 h
GDC-0068 significantly decreased cell viability in the breast cancer cell line MDA-MB-453, with an IC50 of 0.322 μM.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
MDA-MB-361
0.25–10 μM
72 h
GDC-0068 significantly decreased cell viability in the PIK3CA-MT breast cancer brain metastatic cell line MDA-MB-361, with an IC50 of 2.83 μM.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
LNCaP cells
5 μM
To study the mechanism of ipatasertib resistance, it was found that resistant cells showed increased sensitivity to PIM inhibitors
ATP-competitive AKT inhibitors. Nat Commun.
U87 cells
1 mM
To evaluate the effect of Ipatasertib on the Nrf2 signaling pathway in IDH1-mutated and wild-type U87 cells, results showed that Ipatasertib suppressed the expression of Nrf2-related genes.
Clin Cancer Res. 2023 Apr 3;29(7):1305-1316.
NHA cells
1 μM
To evaluate the effect of AKT inhibitor Ipatasertib on IDH1-mutated and wild-type NHA cells, results showed that IDH1-mutated cells were more sensitive to Ipatasertib.
Clin Cancer Res. 2023 Apr 3;29(7):1305-1316.
Hec-1B cells
10 μM
72 h
To investigate the inhibitory effect of Ipatasertib in combination with ascorbate on the proliferation of Hec-1B cells. Results showed that Ipatasertib alone significantly inhibited cell proliferation, and the combination with ascorbate produced a more potent inhibitory effect.
Int J Biol Sci. 2025 Jan 27;21(4):1545-1565.
KLE cells
10 μM
72 h
To investigate the inhibitory effect of Ipatasertib in combination with ascorbate on the proliferation of KLE cells. Results showed that Ipatasertib alone significantly inhibited cell proliferation, and the combination with ascorbate produced a more potent inhibitory effect.
Int J Biol Sci. 2025 Jan 27;21(4):1545-1565.
HCT116
10 μM
0, 6, 12, and 24 h
To study the effect of Ipatasertib on the expression of Akt, FoxO3a, p65, and PUMA, the results showed that Ipatasertib significantly inhibited the phosphorylation of Akt, while activating FoxO3a and p65, and upregulating the expression of PUMA.
Cell Death Dis. 2018 Sep 5;9(9):911.
HCT116
10 μM
12 and 24 h
To study the effect of Ipatasertib on colon cancer cell proliferation, the results showed that Ipatasertib significantly inhibited the proliferation of HCT116, p53−/−, and DLD1 cells, indicating that p53 is dispensable in this process.
Cell Death Dis. 2018 Sep 5;9(9):911.
Ipatasertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MLL-AF9-driven AML model
Oral
65mg/kg
Every other day, for five cycles
To evaluate the effect of ipatasertib combined with selinexor, results showed that the combination significantly prolonged the survival of mice.
Nat Cancer. 2022 Jul;3(7):837-851.
Mice
Ptenpc−/−; Trp53pc−/− prostate cancer model
Oral
100 mg/kg
Daily for six weeks
Inhibited tumor growth, reduced tumor-infiltrating PMN-MDSCs, and increased CD8+ T cells
Nat Cancer. 2023 Aug;4(8):1102-1121.
Mice
PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft model
Oral gavage
100 mg/kg
Daily until the date of death of the last control mouse
In the PIK3CA-mutant MDA-MB-361 breast cancer brain metastasis model, GDC-0068 significantly inhibited tumor growth and significantly extended the survival of mice, with a median survival of 109 days compared to 82.5 days in the control group.
Neuro Oncol. 2019 Nov 4;21(11):1401-1411.
Mice
LNCaP prostate cancer xenograft model
Oral
25 mg/kg
Once daily for 21 days
To evaluate the effect of combined treatment with ipatasertib and PIM inhibitors on resistant tumors, it was found that the combination significantly inhibited tumor growth
ATP-competitive AKT inhibitors. Nat Commun.
CB-17 Scid mice
TS603 xenograft model
Gavage
40 mg/kg
Once on day 15 and day 30
To evaluate the effect of Ipatasertib combined with TMZ on IDH-mutated TS603 xenograft model, results showed that the combination treatment significantly prolonged the survival of the mice.
Clin Cancer Res. 2023 Apr 3;29(7):1305-1316.
Nude mice
Xenograft model
Oral
30 mg/kg
Once daily for 15 consecutive days
To study the antitumor activity of Ipatasertib in vivo, the results showed that Ipatasertib significantly inhibited the growth of WT tumors, but had less effect on PUMA?/? tumors, indicating that PUMA is indispensable for the antitumor effect of Ipatasertib.
Cell Death Dis. 2018 Sep 5;9(9):911.
Ipatasertib 动物研究
Dose
Mice: min = 40 mg/kg[4] (s.c.), max = 100 mg/kg[3] (p.o.)
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