Product Categories

GDC-0980 (RG7422)

GDC-0980 (RG7422) is a potent, selective inhibitor of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ with IC50 of 5 nM, 27 nM, 7 nM, and 14 nM, and also a mTOR inhibitor with K_i of 17 nM.

Catalog No.S2696

2 Reviews

: Tel: +1-832-582-8158[email protected]

GDC-0980 (RG7422) Chemical Structure
Molecular Weight: 498.6

Validation & Quality Control

Customer Reviews(2) in vivo invitation

Quality Control & MSDS

Related Compound Libraries

GDC-0980 (RG7422) is available in the following compound libraries:

Chemical Library (96-well) Inhibitor Library (96-well) Kinase Inhibitor Library (96-well)

Product Information

Compare PI3K Inhibitors

Cat.No.	Product Name	Solubility (25°C)
Cat.No.	Product Name	Water	DMSO	Ethanol
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S1065	GDC-0941	<1 mg/mL	44 mg/mL	<1 mg/mL
S2226	CAL-101 (GS-1101)	<1 mg/mL	83 mg/mL	35 mg/mL
S2247	BKM120 (NVP-BKM120)	<1 mg/mL	82 mg/mL	2 mg/mL
S2638	NU7441 (KU-57788)	<1 mg/mL	3 mg/mL	<1 mg/mL
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S1038	PI-103	<1 mg/mL	24 mg/mL	<1 mg/mL
S1169	TGX-221	<1 mg/mL	12 mg/mL	<1 mg/mL
S2758	Wortmannin	<1 mg/mL	86 mg/mL	<1 mg/mL
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S1072	ZSTK474	<1 mg/mL	21 mg/mL	<1 mg/mL
S1118	XL147	<1 mg/mL	3 mg/mL	<1 mg/mL
S2767	3-Methyladenine	<1 mg/mL	4 mg/mL	4 mg/mL
S1268	IC-87114	<1 mg/mL	0.66 mg/mL	<1 mg/mL
S1410	AS-605240	<1 mg/mL	0.4 mg/mL	<1 mg/mL
S2671	AS-252424	<1 mg/mL	61 mg/mL	<1 mg/mL
S1523	XL765 (SAR245409)	<1 mg/mL	15 mg/mL	<1 mg/mL
S2658	GSK2126458	<1 mg/mL	101 mg/mL	<1 mg/mL
S1205	PIK-75	<1 mg/mL	3 mg/mL	<1 mg/mL
S2743	PF-04691502	<1 mg/mL	14 mg/mL	<1 mg/mL
S1462	AZD6482	<1 mg/mL	82 mg/mL	28 mg/mL
S2628	PF-05212384 (PKI-587)	<1 mg/mL	2 mg/mL	<1 mg/mL
S2696	GDC-0980 (RG7422)	<1 mg/mL	20 mg/mL	<1 mg/mL
S1489	PIK-93	<1 mg/mL	78 mg/mL	<1 mg/mL
S1187	PIK-90	<1 mg/mL	0.28 mg/mL	<1 mg/mL
S2802	BAY80-6946	<1 mg/mL	<1 mg/mL	<1 mg/mL
S1352	TG100-115	<1 mg/mL	9 mg/mL	<1 mg/mL
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S2699	CH5132799	<1 mg/mL	12 mg/mL	<1 mg/mL
S2682	CAY10505	<1 mg/mL	58 mg/mL	<1 mg/mL
S2749	NVP-BGT226	<1 mg/mL	30 mg/mL	<1 mg/mL
S2759	PI3K/HDAC InhibitorⅠ	<1 mg/mL	102 mg/mL	<1 mg/mL
S2207	PIK-293	<1 mg/mL	80 mg/mL	<1 mg/mL
S2739	PKI-402	<1 mg/mL	0.4 mg/mL	<1 mg/mL
S2870	TG 100713	<1 mg/mL	2 mg/mL	<1 mg/mL
S8002	GSK2636771	<1 mg/mL	87 mg/mL	19 mg/mL
S7028	IPI-145 (INK1197)	<1 mg/mL	84 mg/mL	<1 mg/mL

Research Area
Research Area
GDC-0980 (RG7422) Mechanism
GDC-0980 (RG7422) Mechanism
The receptor-regulated class I PI3K are heterodimeric enzymes, consisting of a 110-kDa catalytic subunit and a regulatory subunit. Different from p110α, -β, and -δ isoforms, the p110γ isoform tightly binds to the p101 regulatory subunit. The p101 structure indicates that an N-terminal domain mediates heterodimerization with the p110γ subunit, and a C-terminal interaction domain mediates the binding to Gβγ complexes. ^[1] The ATP binding site of PI3K-gamma catalytic domain is located in a cleft between the N- and the C-terminal lobes of the catalytic domain.
The crystal structure indicates that GDC-0980 binds in the active site of PI3K-gamma catalytic domain. Specifically, the morpholine ring of GDC-0980 is anchored to the hinge region by making a hydrogen bond from the oxygen atom to the backbone of Val882. Besides, the aminopyrimidine extends along the cleft and forms two hydrogen bonds from NH2 to the carbonyl oxygens of Asp841 and Asp964. The piperazine moiety of GDC-0980 points towards the solvent and interacts with Lys802 via a hydrogen bond. The binding mode results in greater affinity of PI3K enzyme for GDC-0980 than ATP. ^[2]
References
[1] Voigt P, et al. J Biol Chem. 2005, 280(6), 5121-5127.
[2] Sutherlin DP, et al. J Med Chem. 2011, 54(21), 7579-7587.

Combination Therapy

Dr. Antonino Maria Sparta demonstrates a breakthrough in leukemia research by utilizing two inhibitors produced by Selleck Chemicals.

Product Description

Biological Activity Protocol Chemical Information Customer Reviews Tech Support & FAQs

Biological Activity

Description	GDC-0980 (RG7422) is a potent, selective inhibitor of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ with IC50 of 5 nM, 27 nM, 7 nM, and 14 nM, and also a mTOR inhibitor with K_i of 17 nM.
Targets	PI3Kα	PI3Kβ	PI3Kδ	PI3Kγ	mTOR
IC50	5 nM	27 nM	7 nM	14 nM	17 nM (K_i) ^[1]
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]
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]
Clinical Trials	GDC-0980 is currently in Phase II clinical trials in patients with recurrent or persistent endometrial carcinoma.
Features	GDC-0980 (RG7422) is a potent, selective, and orally available inhibitor of PI3Kα, β, δ, γ and mTOR.

Protocol(Only for 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 K_m for ATP of 6.1 μM.

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 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.
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.

References

Chemical Information

Download GDC-0980 (RG7422) SDF

Molecular Weight (MW)	498.6
Formula	C₂₃H₃₀N₈O₃S
CAS No.	1032754-93-0, 1309043-78-4, 1309384-87-9
Synonyms	N/A

Solubility (25°C) DMSO 20 mg/mL Water <1 mg/mL Ethanol <1 mg/mL
Storage	2 years -20°CPowder
	2 weeks4°Cin DMSO
	6 months-80°Cin DMSO

Chemical Name	(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

Molarity Calculator Dilution Calculator Molecular Weight Calculator

Research Area

Customer Reviews (2)

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Rating

Source

Dr.Wang Wei from NanFang Hospital. 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.

Click to enlarge

Rating

Source

Dr. Zhang of Tianjin Medical University. 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.

Tech Support & FAQs

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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GDC-0980 (RG7422)