Apitolisib (GDC-0980, RG7422)

Apitolisib (GDC-0980, RG7422)は、PI3Kα、β、δと、27nM、7nMと14nM、5nMのIC50によるγの強力で、選択的で、口で利用できる阻害剤、更には17nMのKiによるmTORキナーゼ阻害剤です。

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Apitolisib (GDC-0980, RG7422) 化学構造
分子量: 498.6

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製品説明

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製品の説明

生物活性

製品説明 Apitolisib (GDC-0980, RG7422)は、PI3Kα、β、δと、27nM、7nMと14nM、5nMのIC50によるγの強力で、選択的で、口で利用できる阻害剤、更には17nMのKiによるmTORキナーゼ阻害剤です。
ターゲット PI3Kα PI3Kβ PI3Kδ PI3Kγ mTOR
IC50 5 nM 27 nM 7 nM 14 nM 17 nM (Ki) [1]
In vitro試験 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試験 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]
臨床試験 GDC-0980 is currently in Phase II clinical trials in patients with recurrent or persistent endometrial carcinoma.
特集 A potent, selective, and orally available inhibitor of PI3Kα, β, δ, γ and mTOR.

プロトコル (参考用のみ)

キナーゼアッセイ: [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.

細胞アッセイ: [1]

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.

動物実験: [1]

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.
製剤 GDC-0980 is dissolved in 0.5% methylcellulose with 0.2% Tween-80 (MCT).
投薬量 ≤7.5 mg/kg
投与方法 Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Apitolisib (GDC-0980, RG7422) SDF
分子量 498.6
化学式

C23H30N8O3S

CAS No. 1032754-93-0
保管 2年-20℃
6月-80℃in solvent
別名 GNE 390
溶解度 (25°C) * In vitro DMSO 20 mg/mL (40.11 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose/0.2% Tween 80 30 mg/mL
* <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.
化学名 (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one

カスタマーフィードバック (4)


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Rating
Source Breast Cancer Res, 2014, 16(4), 406. Apitolisib (GDC-0980, RG7422) purchased from Selleck
Method Immunoblots
Cell Lines AR + TNBC cells
Concentrations 300 nM
Incubation Time 48 h
Results As anticipated, GDC-0980 was more effective at decreasing mTOR activity, measured by the decrease in levels of phosphorylated S6. Interestingly, GDC-0980 treatment alone decreased AR levels and this effect could be enhanced further by the addition of CDX, suggesting that mTOR activity may contribute to elevated AR protein levels, similar to the signaling observed in prostate cancer.

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Rating
Source PLoS One, 2014, 9(9), e105919. Apitolisib (GDC-0980, RG7422) purchased from Selleck
Method Immunoblots
Cell Lines H2596, H513 cells
Concentrations 0.1-0.5 uM
Incubation Time 48 h
Results The levels of cyclin D1, which is a G0/G1 cell cycle regulator were decreased in cells treated with ARQ 197, GDC-0980 or NVP-BEZ235, in a dose dependent manner. In the case of NVP-BEZ235 the effect was much more pronounced in H513 cells compared to H2596 (B, C). However, the combination of ARQ 197/GDC-0980 and ARQ 197/NVP-BEZ235 induced the largest decrease in cyclin D1. The combinatorial treatment of ARQ 197/GDC-0980 and ARQ 197/NVP-BEZ235 however induced significant levels of cleaved PARP in both MPM cell lines. Individual treatment with GDC-0980 or NVP-BEZ235 had little effect as evidenced from cleaved PARP levels.

Click to enlarge
Rating
Source Dr.Wang Wei from NanFang Hospital. Apitolisib (GDC-0980, RG7422) purchased from Selleck
Method MTT assay/Western blotting
Cell Lines A549 cell
Concentrations 0-3 μM
Incubation Time 72 h
Results PI3K/mTOR inhibitor GDC-0980 supresses cell growth of A549 by inhibiting Akt /mTOR signaling pathway.

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Rating
Source Dr. Zhang of Tianjin Medical University. Apitolisib (GDC-0980, RG7422) purchased from Selleck
Method Western Blot
Cell Lines A549 cells
Concentrations 0-10 μM
Incubation Time 3 h
Results GDC0980 treatment resulted in a reduction of AKT phosphorylation.

文献中の引用 (5)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
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