Home PI3K/Akt/mTOR PI3K inhibitor - mTOR inhibitor - Autophagy activator - Apoptosis related activator Apitolisib (GDC-0980) For research use only.

Apitolisib (GDC-0980)

Synonyms: RG7422, GNE 390

Apitolisib (GDC-0980, RG7422, GNE 390) is a potent, class I PI3K inhibitor for PI3Kα/β/δ/γ with IC50 of 5 nM/27 nM/7 nM/14 nM in cell-free assays, respectively. Also a mTOR inhibitor with Ki of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases. Apitolisib activates autophagy and apoptosis simultaneously in pancreatic cancer cells. Phase 2.

Apitolisib (GDC-0980) Chemical Structure

Apitolisib (GDC-0980) Chemical Structure

CAS: 1032754-93-0

Selleck's Apitolisib (GDC-0980) has been cited by 32 publications

Purity & Quality Control

Batch: Purity: 99.76%
99.76

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Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
insect cells Function assay 30 mins Inhibition of human recombinant mTOR expressed in insect cells assessed as phosphorylation of recombinant (GFP)-4-EBP1 measured after 30 mins by fluorescence polarization assay, Ki=0.017μM 21981714
PC3 Function assay Inhibition of PIK3 gamma-mediated Akt phosphorylation at Ser473 in human PC3 cells by ELISA, IC50=0.036μM 21981714
MCF7.1 Antiproliferative assay Antiproliferative activity against human MCF7.1 cells expressing HER2 gene after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.255μM 21981714
PC3 Antiproliferative assay Antiproliferative activity against human PC3 cells after overnight incubation by CellTiter-Glo luminescence assay, IC50=0.307μM 21981714
PC3 Antitumor assay 1 mg/kg 14 days Antitumor activity against human PC3 cells xenografted in athymic nu/nu mouse assessed as delay in tumor growth at 1 mg/kg, po qd for 14 days 21981714
MCF7-neo Antitumor assay 1 mg/kg 22 days Antitumor activity against human MCF7-neo cells expressing HER2 gene xenografted in athymic nu/nu mouse assessed as delay in tumor growth at 1 mg/kg, po qd for 22 days 21981714
PC3 Antitumor assay Antitumor activity against human PC3 cells xenografted in athymic nu/nu mouse assessed as tumor regression at maximum tolerated dose 21981714
MCF7-neo Antitumor assay Antitumor activity against human MCF7-neo cells expressing HER2 gene xenografted in athymic nu/nu mouse assessed as tumor regression at maximum tolerated dose 21981714
PC3 Antitumor assay 14 days Antitumor activity against human PC3 cells xenografted in athymic nu/nu mouse assessed as tumor stasis at maximum tolerated dose measured on day 14 21981714
MCF7-neo Antitumor assay 22 days Antitumor activity against human MCF7-neo cells expressing HER2 gene xenografted in athymic nu/nu mouse assessed as tumor stasis at maximum tolerated dose measured on day 22 21981714
PC3 Function assay 10 mg/kg 6 hrs Inhibition of mTORC2 in human PC3 cells xenografted mouse assessed as reduction of phosphorylated Akt level at 10 mg/kg, po after 6 hrs 23199076
PC3 Function assay 10 mg/kg 6 hrs Inhibition of mTORC1 in human PC3 cells xenografted mouse assessed as reduction of phosphorylated p70S6K level at 10 mg/kg, po after 6 hrs 23199076
insect cells Function assay 30 mins Inhibition of human recombinant mTOR (1360 to 2549 residues) expressed in insect cells assessed as inhibition of GFP-labeled 4-EBP1 phosphorylation at Thr-37/46 residues incubated for 30 mins by FRET assay, Ki=0.017μM 27096040
PC3 Antiproliferative assay 3 days Antiproliferative activity against human PC3 cells after 3 days by CellTitre-Glo assay, EC50=0.31μM 27096040
VERO-E6 Toxicity assay 48 hrs Toxicity CC50 against VERO-E6 cells determined at 48 hours by high content imaging (same conditions as 2_LEY without exposure to 0.01 MOI SARS CoV-2 virus), CC50=0.5μM ChEMBL
VERO-E6 Function assay 48 hrs Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging, IC50=2.31μM ChEMBL
Click to View More Cell Line Experimental Data

Biological Activity

Description Apitolisib (GDC-0980, RG7422, GNE 390) is a potent, class I PI3K inhibitor for PI3Kα/β/δ/γ with IC50 of 5 nM/27 nM/7 nM/14 nM in cell-free assays, respectively. Also a mTOR inhibitor with Ki of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases. Apitolisib activates autophagy and apoptosis simultaneously in pancreatic cancer cells. Phase 2.
Features A potent, selective, and orally available inhibitor of PI3Kα, β, δ, γ and mTOR.
Targets
p110α [1]
(Cell-free assay)		 p110δ [1]
(Cell-free assay)		 p110γ [1]
(Cell-free assay)		 mTOR [1]
(Cell-free assay)		 p110β [1]
(Cell-free assay)
5 nM 7 nM 14 nM 17 nM(Ki app) 27 nM
In vitro
In vitro GDC-0980 shows the potent and selective inhibitory activities against class I PI3K and mTOR kinase versus a large panel of kinases with Ki of 17 nM for mTOR and IC50 of 5 nM, 27 nM, 7 nM, and 14 nM for PI3Kα, β, δ, and γ, respectively. [1] In vitro, GDC-0980 significantly inhibits cell proliferation in PC3 and MCF7 cells with IC50 of 307 nM and 255 nM, respectively. [1] A recent study shows that GDC-0980 reduces cancer cell viability by inhibiting cell-cycle procession and inducing apoptosis with most potency in prostate (IC50 < 200 nM 50%), <500 nM 100%), breast (IC50 <200 nM 37%, <500 nM 78%) and NSCLC lines (IC50 <200 nM 29%, <500 nM 88%) and less potency in pancreatic (IC50 <200 nM 13%, <500 nM 67%) and melanoma cell lines (IC50 <200 nM 0%, <500 nM 33%). [2]
Kinase Assay Enzymatic activity
Enzymatic activity of the Class I PI3K isoforms is measured using a fluorescence polarization assay that monitors formation of the product 3,4,5-inositoltriphosphate molecule as it competes with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. An increase in phosphatidyl inositide-3-phosphate product results in a decrease in fluorescence polarization signal as the labeled fluorophore is displaced from the GRP-1 protein binding site. Class I PI3K isoforms are expressed and purified as heterodimeric recombinant proteins. PI3K isoforms are assayed under initial rate conditions in the presence of 10 mM Tris (pH 7.5), 25 μM ATP, 9.75 μM PIP2, 5% glycerol, 4 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 2% (v/v) DMSO at the following concentrations for each isoform: PI3Kα,β at 60 ng/mL; PI3Kγ at 8 ng/mL; PI3Kδ at 45 ng/mL. After assay for 30 minutes at 25°C, reactions are terminated with a final concentration of 9 mM EDTA, 4.5 nM TAMRA-PIP3, and 4.2 μg/mL GRP-1 detector protein before reading fluorescence polarization on an Envision plate reader. IC50s are calculated from the fit of the dose−response curves to a 4-parameter equation.Human recombinant mTOR(1360−2549) is expressed and purified from insect cells and assayed using a Lanthascreen fluorescence resonance energy transfer format in which phosphorylation of recombinant green fluorescent protein (GFP)-4-EBP1 is detected using a terbium-labeled antibody to phospho-threonine 37/46 of 4-EBP1. Reactions are initiated with ATP and conducted in the presence of 50 mM Hepes (pH 7.5), 0.25 nM mTOR, 400 nM GFP-4E-BP1, 8 μM ATP, 0.01% (v/v) Tween 20, 10 mM MnCl2, 1 mM EGTA, 1 mM dithiothreitol, and 1% (v/v) DMSO. Assays are conducted under initial rate conditions at room temperature for 30 minutes before terminating the reaction and detecting product in the presence of 2 nM Tb-anti-p4E-BP1 antibody and 10 mM EDTA. Dose−response curves are fit to an equation for competitive tight-binding inhibition and apparent Ki' s are calculated using the determined Km for ATP of 6.1 μM.
Cell Research Cell lines PC3 and MCF7.1
Concentrations 0 to 10 μM
Incubation Time 72 hours or 96 hours
Method Antiproliferative cellular assays are conducted using PC3 and MCF7.1 human tumor cell lines. MCF7.1 is an in vivo selected line and originally derived from the parental human MCF7 breast cancer cell line. Cell lines are cultured in RPMI supplemented with 10% fetal bovine serum, 100 units/mL penicillin, and 100 μg/mL streptomycin, 10 mM HEPES, and 2 mM glutamine at 3°C under 5% CO2. MCF7.1 cells or PC3 cells are seeded in 384-well plates in media at 1000 cells/well or 3000 cells/well, respectively, and incubated overnight prior to the addition of GDC-0980 to a final DMSO concentration of 0.5% v/v. MCF7.1 cells and PC3 cells are incubated for 3 days and 4 days, respectively, prior to the addition of CellTiter-Glo reagen and reading of luminescence using an Analyst plate reader. For antiproliferative assays, a cytostatic agent such as aphidicolin and a cytotoxic agent such as staurosporine are included as controls. Dose−response curves are fit to a 4-parameter equation and relative IC50s are calculated using Assay Explorer software.
Experimental Result Images Methods Biomarkers Images PMID
Growth inhibition assay Cell viability 25221930
Western blot p-AKT / AKT / p-S6RP / S6RP / p-4EBP / 4EBP / p-eNOS / eNOS 23814482
In Vivo
In vivo In both PC-3 and MCF-7 neo/HER2 xenograft models, GDC-0980 at a dose of 1 mg/kg, exhibits significant antitumor activity by causing tumor growth delay. Furthermore, GDC-0980 results in tumor stasis or regressions at the maximum tolerated dose of 7.5 mg/kg. [1] In mice, intravenous GDC-0980 administration at 1 mg/kg leads to low clearance (Clp: 9.2 mL/min/kg, Vss: 1.7 L/kg). While, oral administration at 5 mg/kg in 80% PEG400 and at 50 mg/kg as a crystalline suspension in 0.5% methylcellulose/0.2% Tween-80 also results in favorable pharmacokinetic parameters. [1]
Animal Research Animal Models PC3 and MCF7.1 cells are injected s.c. into the right hind flank of athymic nu/nu (nude) mice.
Dosages ≤7.5 mg/kg
Administration Administered via p.o.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01487239 Completed Healthy Volunteer Genentech Inc. December 2011 Phase 1
NCT01455493 Completed Endometrial Carcinoma Genentech Inc. December 2011 Phase 2
NCT01442090 Completed Renal Cell Carcinoma Genentech Inc. October 2011 Phase 2
NCT01254526 Completed Breast Cancer Genentech Inc. December 2010 Phase 1
NCT00854126 Completed Non-Hodgkin''s Lymphoma Solid Cancers Genentech Inc. May 2009 Phase 1
NCT00854152 Completed Non-Hodgkin''s Lymphoma Solid Cancers Genentech Inc. March 2009 Phase 1

Chemical lnformation & Solubility

Molecular Weight 498.6 Formula

C23H30N8O3S
CAS No. 1032754-93-0 SDF Download Apitolisib (GDC-0980) SDF
Smiles CC1=C(SC2=C1N=C(N=C2N3CCOCC3)C4=CN=C(N=C4)N)CN5CCN(CC5)C(=O)C(C)O
Storage (From the date of receipt)

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Batch:

DMSO : 27 mg/mL ( (54.15 mM)； Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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