Apitolisib (GDC-0980)

Catalog No.S2696 Batch:S269602

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Technical Data

Formula

C23H30N8O3S
Molecular Weight 498.6 CAS No. 1032754-93-0
Solubility (25°C)* In vitro DMSO 20 mg/mL (40.11 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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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.
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 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]
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]
Features A potent, selective, and orally available inhibitor of PI3Kα, β, δ, γ and mTOR.

Protocol (from reference)

Kinase Assay:[1]
  • 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 Assay:[1]
  • 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.
Animal Study:[1]
  • 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.

Customer Product Validation

Data from [Data independently produced by Breast Cancer Res, 2014, 16(4), 406]

Data from [Data independently produced by PLoS One, 2014, 9(9), e105919]

, , Dr.Wang Wei from NanFang Hospital

, , Dr. Zhang of Tianjin Medical University

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

Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer models improves antitumor efficacy and promotes cell apoptosis [ Mol Oncol, 2024, 10.1002/1878-0261.13577] PubMed: 38225213
Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy [ Cell Metab, 2022, S1550-4131-2200411-9] PubMed: 36257316
Distinctive molecular features of regenerative stem cells in the damaged male germline [ Nat Commun, 2022, 13(1):2500] PubMed: 35523793
Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing [ Theranostics, 2022, 12(4):1659-1682] PubMed: 35198063
Cancer genes disfavoring T cell immunity identified via integrated systems approach [ Cell Rep, 2022, 40(5):111153] PubMed: 35926468
Therapeutic Targeting of Stromal-Tumor HGF-MET Signaling in an Organotypic Triple-Negative Breast Tumor Model [ Mol Cancer Res, 2022, 20(7):1166-1177] PubMed: 35348758
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening [ Cancers (Basel), 2022, 14(6)1575] PubMed: 35326726
Culture and multiomic analysis of lung cancer patient-derived pleural effusions revealed distinct druggable molecular types [ Sci Rep, 2022, 12(1):6345] PubMed: 35428753
Multifocal Organoid Capturing of Colon Cancer Reveals Pervasive Intratumoral Heterogenous Drug Responses [ Adv Sci (Weinh), 2021, e2103360] PubMed: 34918496
Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer [ Commun Biol, 2021, 4(1):1333] PubMed: 34824367

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