Apitolisib (GDC-0980)

別名: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)化学構造

CAS No. 1032754-93-0

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 51000 国内在庫あり
JPY 25500 国内在庫あり
JPY 40500 国内在庫あり
JPY 115500 国内在庫あり
JPY 508500 国内在庫なし(納期7~10日)

代表番号: 045-509-1970|電子メール:[email protected]
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Apitolisib (GDC-0980)関連製品

シグナル伝達経路

PI3K阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
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 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 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 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
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
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 Function assay Inhibition of PIK3 gamma-mediated Akt phosphorylation at Ser473 in human PC3 cells by ELISA, IC50=0.036μM 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 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
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生物活性

製品説明 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.
特性 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.
細胞実験 細胞株 PC3 and MCF7.1
濃度 0 to 10 μM
反応時間 72 hours or 96 hours
実験の流れ 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.
実験結果図 Methods Biomarkers 結果図 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]
動物実験 動物モデル PC3 and MCF7.1 cells are injected s.c. into the right hind flank of athymic nu/nu (nude) mice.
投与量 ≤7.5 mg/kg
投与経路 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

化学情報

分子量 498.6 化学式

C23H30N8O3S

CAS No. 1032754-93-0 SDF Download Apitolisib (GDC-0980) SDFをダウンロードする
Smiles CC1=C(SC2=C1N=C(N=C2N3CCOCC3)C4=CN=C(N=C4)N)CN5CCN(CC5)C(=O)C(C)O
保管

In vitro
Batch:

DMSO : 27 mg/mL ( (54.15 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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