Apitolisib (GDC-0980, RG7422)

Catalog No.S2696 Synonyms: GNE 390

Molecular Weight(MW): 498.6

Apitolisib (GDC-0980, RG7422) 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 K_i of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases. Phase 2.

5 Customer Reviews

Inhibition of PI3Kγ or PI3Kδ significantly decreased the migration of JVM3 cells. JVM3 cells were cultured in medium or stimulated for 24 h with CD40L/IL-4 and then incubated with the PI3Kγ-specific inhibitor CZC24832 (2 µM), the PI3Kδ-specific inhibitor idelalisib (1 µM), dual PI3Kδ/γ inhibitor duvelisib (1 µM), or the pan-PI3K inhibitor GDC0980 (1 µM) and subjected to a transwell migration assay. DMSO served as the vehicle control for the inhibitors, while SDF1α (100 ng/ml) served as the chemoattractant (n = 7).

Leukemia, 2018, 32(9):1958-1969. Apitolisib (GDC-0980, RG7422) purchased from Selleck.

Immunoblots from AR + TNBC cell lines treated with either CDX (25 uM), GDC-0941 (300 nM) or GDC0980 (100 nM) as single agents or CDX in combination with either GDC-0941 or GDC-0980 for 48 h analyzed for AR, p-AKT, AKT, p-S6, S6 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein.

Breast Cancer Res 2014 16(4), 406. Apitolisib (GDC-0980, RG7422) purchased from Selleck.
H2596 (B) and H513 (C) cells, were treated with ARQ 197, GDC-0980, NVP-BEZ235 alone and in combination for 48 h. Cell lysates were prepared and immunoblotted for total PARP, cleaved PARP, cyclin D1 and actin as a loading control. H2596 cells treated with ARQ 197, GDC-0980, NVP-BEZ235 alone and in combination for 48 h, the cells were then stained with Annexin V-FITC/PI and analyzed by flow cytometry.

PLoS One 2014 9(9), e105919. Apitolisib (GDC-0980, RG7422) purchased from Selleck.

PI3K/mTOR inhibitor GDC-0980 supresses cell growth of A549 by inhibiting Akt/mTOR signaling pathway. A. A549 cells were incubated for 72 hours with various concentrations of GDC-0980. Cell growth was determined by MTT assay. B. A549 cells were incubated with GDC-0980 for 1 hour. The cell lysates were harvested and phosphorylation of indicated proteins was determined by Western blotting.

Dr.Wang Wei from NanFang Hospital. Apitolisib (GDC-0980, RG7422) purchased from Selleck.
After starved in serum-free medium for 24h,A549 cells incubated with the indicated concentrations of GDC-0980 for 3h,followed by 20-minute stimolation of 100ng/ml EGF.

Dr. Zhang of Tianjin Medical University. Apitolisib (GDC-0980, RG7422) purchased from Selleck.

Purity & Quality Control

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Biological Activity

Description

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

GDC-0980 shows the potent and selective inhibitory activities against class I PI3K and mTOR kinase versus a large panel of kinases with K_i 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]

Cell Data

Cell Lines	Assay Type	Incubation Time	Activity Description	PMID
insect cells	MnrmSpVv[3Srb36gZZN{[Xl?	NIS3[VE{OCCvaX7z	NEj4WoNKdmirYnn0bY9vKG:oIHj1cYFvKHKnY3;tZolv[W62IH3UU3Ih\XiycnXzd4VlKGmwIHnud4VkfCClZXzsd{Bie3Onc4Pl[EBieyCyaH;zdIhwenmuYYTpc44hd2ZicnXjc41jcW6jboSgLGdHWClvND3FRnAyKG2nYYP1doVlKGGodHXyJFMxKG2rboOgZpkh\my3b4Lld4NmdmOnIIDvcIFzcXqjdHnvckBie3OjeTygT4k:OC5yMUeg{txO	NGHJV\|YzOTl6MUexOC=>
human PC3 cells	MkPaSpVv[3Srb36gZZN{[Xl?		NWTDNHVWUW6qaXLpeIlwdiCxZjDQTWs{KGejbX3hMY1m\GmjdHXkJGFsfCCyaH;zdIhwenmuYYTpc44h[XRiU3XyOFc{KGmwIHj1cYFvKFCFMzDj[YxteyCkeTDFUGlUSSxiSVO1NF0xNjB\|NjFOwG0>	M4jXPFIyQThzN{G0
human MCF7.1 cells	Ml3DVJJwdGmoZYLheIlwdiCjc4PhfS=>		MVvBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKE2FRkeuNUBk\WyuczDlfJBz\XO\|aX7nJGhGWjJiZ3Xu[UBi\nSncjDveoVzdmmpaISgbY5kfWKjdHnvckBjgSCFZXzsWIl1\XJvR3zvJIx2dWmwZYPj[Y5k\SCjc4PhfUwhUUN3ME2wMlI2PSEQvF2=	MVeyNVk5OTdzNB?=
human PC3 cells	NFzEWYhRem:uaX\ldoF1cW:wIHHzd4F6		NG[4flFCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIGDDN{Bk\WyuczDh[pRmeiCxdnXycolocHRiaX7jeYJifGmxbjDifUBE\WyuVHn0[ZIuT2yxIHz1cYlv\XOlZX7j[UBie3OjeTygTWM2OD1yLkOwO{DPxE1?	M3;iRlIyQThzN{G0

... Click to View More Cell Line Experimental Data

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 (Cl_p: 9.2 mL/min/kg, V_ss: 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]

Protocol

Kinase Assay:^[1]	+ Expand 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 K_m for ATP of 6.1 μM.
Cell Research:^[1]	+ Expand 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. (Only for Reference)
Animal Research:^[1]	+ Expand Animal Models: PC3 and MCF7.1 cells are injected s.c. into the right hind flank of athymic nu/nu (nude) mice. Formulation: GDC-0980 is dissolved in 0.5% methylcellulose with 0.2% Tween-80 (MCT). Dosages: ≤7.5 mg/kg Administration: Administered via p.o. (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	20 mg/mL (40.11 mM)
	Water	Insoluble
	Ethanol	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 0.5% methylcellulose+0.2% Tween 80 For best results, use promptly after mixing.	30 mg/mL

* 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.

Chemical Information Download Apitolisib (GDC-0980, RG7422) SDF

Molecular Weight	498.6
Formula	C₂₃H₃₀N₈O₃S
CAS No.	1032754-93-0
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	GNE 390

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2018-11-16)

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
NCT01473316	Completed	Healthy Volunteer	Genentech Inc.	November 2011	Phase 1
NCT01442090	Completed	Renal Cell Carcinoma	Genentech Inc.	October 2011	Phase 2
NCT01437566	Completed	Breast Cancer	Genentech Inc.	October 2011	Phase 2
NCT01301716	Completed	Solid Cancers	Genentech Inc.	September 2011	Phase 1

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PI3K Signaling Pathway Map

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FDA-approved PI3K Inhibitor

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Apitolisib (GDC-0980, RG7422)