Omipalisib (GSK2126458)

Name: Omipalisib (GSK2126458)
Brand: Selleck Chemicals
SKU: S2658
Rating: 5 (19 reviews)

For research use only. Not for use in humans.

Catalog No.S2658 Synonyms: GSK458

19 publications

Omipalisib (GSK2126458) Chemical Structure

Molecular Weight(MW): 505.5

Omipalisib (GSK2126458, GSK458) is a highly selective and potent inhibitor of p110α/β/δ/γ, mTORC1/2 with K_i of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM in cell-free assays, respectively. Phase 1.

Selleck's Omipalisib (GSK2126458) has been cited by 19 publications

Nat Commun, 2020, 11(1):71

PubMed: 31900415 ( click the link to review the publication )

J Thorac Oncol, 2019, 14(6):1061-1076

PubMed: 30825612 ( click the link to review the publication )

J Thorac Oncol, 2019, 14(6):1061-1076

PubMed: 30825612 ( click the link to review the publication )

Clin Cancer Res, 2019, 25(5):1639-1649

PubMed: 30504425 ( click the link to review the publication )

Nat Commun, 2018, 9(1):4583

PubMed: 30389923 ( click the link to review the publication )

Nat Commun, 2018, 9(1):1816

PubMed: 29739933 ( click the link to review the publication )

Cancer Genomics Proteomics, 2018, 15(4):239-248

PubMed: 29976629 ( click the link to review the publication )

Nat Commun, 2017, 8(1):1278

PubMed: 29097657 ( click the link to review the publication )

Cancer Lett, 2017, 406:47-53

PubMed: 28797845 ( click the link to review the publication )

Neuro Oncol, 2016, 18(4):528-37

PubMed: 26354928 ( click the link to review the publication )

J Proteome Res, 2016, 15(12):4490-4504

PubMed: 27794612 ( click the link to review the publication )

Mol Cancer Ther, 2015, 14(2):429-39

PubMed: 25504751 ( click the link to review the publication )

Mol Cancer Ther, 2015, 14(1):298-306

PubMed: 25344583 ( click the link to review the publication )

J Pharmaceut Biomed, 2015, 107:403-8

PubMed: ( click the link to review the publication )

J Pharm Biomed Anal, 2015, 107:403-8

PubMed: 25659532 ( click the link to review the publication )

Cancer Cell Int, 2014, 14(1):90

PubMed: 25298748 ( click the link to review the publication )

Am J Transl Res, 2014, 6(5):471-493

PubMed: ( click the link to review the publication )

Proc Natl Acad Sci USA, 2013, 110(10):4015-20

PubMed: 23431193 ( click the link to review the publication )

J Pharmacol Exp Ther, 2013, 347(3):669-80

PubMed: 24068833 ( click the link to review the publication )

Purity & Quality Control

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Biological Activity

Description

Targets

p110α ^[1] (Cell-free assay)	p110δ ^[1] (Cell-free assay)	p110γ ^[1] (Cell-free assay)	p110β ^[1] (Cell-free assay)	mTORC1 ^[1] (Cell-free assay)	View More
0.019 nM(Ki)	0.024 nM(Ki)	0.06 nM(Ki)	0.13 nM(Ki)	0.18 nM(Ki)	View More

In vitro

GSK2126458 potently inhibits the activity of common activating mutants of p110α (E542K, E545K, and H1047R) found in human cancer with K_i of 8 pM, 8 pM and 9 pM, respectively. ^[1] GSK2126458 causes a significant reduction in the levels of pAkt-S473 with remarkable potency in T47D and BT474 cells with IC50 of 0.41 nM and 0.18 nM, respectively. Furthermore, GSK2126458 leads to a G1 cell cycle arrest and produces the inhibitory effect on cell proliferation in a large panel of cell lines, including T47D and BT474 breast cancer lines with IC50 of 3 nM and 2.4 nM, respectively. ^[1]

Assay

Methods	Test Index	PMID
Western blot	p-AKT / AKT / p-RPS6 / RPS6 / p-4E-BP1 / 4E-BP1 ; PubMed: 31069214 Front Chem The suppressive effect of GSK2126458 on the phosphorylation of Akt, S6 Ribosomal protein, and 4E-BP1 in PC3 cells following 3 h-treatment: The levels of phos-Akt (Ser473), phos-Akt (Thr308), phos-S6 ribosomal protein (Ser235/236), and phos-4E-BP1 (Thr37/46) in different groups were determined viaWestern blot assay.	31069214
Growth inhibition assay	IC50; PubMed: 26148118 PLoS One IC50 values (50% inhibition of thymidine incorporation) are shown for BEZ235 (BEZ), GSK2126458 (GSK) and AZD8055 (AZD). Cells were treated with drugs for 3 days and cell proliferation was measured by the thymidine incorporation assay. Results are shown as the mean ± standard error from triplicate experiments.	26148118

In vivo

In a BT474 human tumor xenograft model, GSK2126458 treatment results in a dose-dependent reduction in pAkt-S473 levels, and exhibited dose-dependent tumor growth inhibition at a low dose of 300 μg /kg. Besides, GSK2126458 shows low blood clearance and good oral bioavailability in four preclinical species (mouse, rat, dog, and monkey). ^[1]

Protocol

Kinase Assay:^[1]	- Collapse HTRF In vitro Profiling Assays for PI3K Inhibition : Compounds are serially diluted (3-fold in 100% DMSO) across a 384-well polypropylene mother plate from column 1 to column 12 and column 13 to column 24, to yield 11 concentrations for GSK2126458. Columns 6 and 18 contain only DMSO. Once titrations are made, 0.05μL is transferred to a 384-well low-volume assay plate. This assay plate contains three pharmacological controls (known PI3K inhibitors) and 3 assay controls: (1) Enzyme without inhibitor; (2) Buffer minus enzyme, and (3) Buffer minus enzyme plus native PIP3. DMSO is stamped into all wells of columns 6 and 18. PIP3 is added at 40 μM in 1X Reaction buffer (1μL of 200 μM PIP3) to alternating rows of column 18 (wells 18 B, D, F, H, J, L, N, P). The no-enzyme control reactions are run in wells 18 A, C, E, G, I, K, M, O (0.1μL of 100% DMSO). The PI3-Kinase profiling assay is optimized using the HTRF kit. The assay kit contains seven reagents: 1) 4X Reaction Buffer; 2) native PIP2 (substrate); 3) Stop A (EDTA); 4) Stop B (Biotin-PIP3); 5) Detection Mix A (Streptavidin-APC); 6) Detection Mix B (Eu-labeled Anti-GST plus GST-tagged PHdomain); 7) Detection Mix C (KF). PI3Kinase Reaction Buffer is prepared by diluting the stock 1:4 with de-ionized water. Freshly prepared DTT is added at a final concentration of 5 mM on the day of use. Enzyme addition and compound pre-incubation are initiated by the addition of 2.5μL of PI3K (at twice its final concentration) in 1X reaction buffer to all wells using a Multidrop Combi. Plates are incubated at room temperature for 15 minutes. Reactions are initiated by addition of 2.5μL of 2X substrate solution (PIP2 and ATP in 1X reaction buffer) using a Multidrop Combi. Plates are incubated at room temperature for one hour. Reactions are quenched by the addition of 2.5μL of stop solution (Stop A and Stop B pre-mixed at a ratio of 5:1, respectively) to all wells using the Multidrop Combi. The quenched reactions are then processed to detect product formation by adding 2.5μL of Detection Solution to all wells using the Mulitdrop Combi (Detection mix C, Detection mix A, and Detection mix B combined together in an 18:1:1 ratio, i.e.: for a 6000 μL total volume, mix 5400 μL Detection mix C, 300μL Detection mix A, and 300 μL Detection mix B. Note: this solution should be prepared 2 hours prior to use). Following a one hour incubation in the dark, the HTRF signal is measured on the Envision plate reader set for 330nm excitation and dual emission detection at 620nm (Eu) and 665nm (APC).
Cell Research:^[1]	- Collapse Cell lines: BT474, HCC1954 and T-47D cells Concentrations: 0-1 μM Incubation Time: 72 hours Method: BT474, HCC1954 and T-47D (human breast) are cultured in RPMI-1640 containing 10% fetal bovine serum at 37 °C in 5% CO₂ incubator. Cells are split into T75 flask two to three days prior to assay set up at density which yields approximately 70-80% confluence at time of harvest for assay. Cells are harvested using 0.25% trypsin-EDTA. Cell counts are performed on cell suspension using Trypan Blue exclusion staining. Cells are then plated in 384 well black flat bottom polystyrene in 48 μL of culture media per well at 1,000 cells/well. All plates are placed at 5% CO₂, 37 °C overnight and GSK2126458 is added the following day. One plate is treated with CellTiter-Glo for a day 0 (t=0) measurement and read as described below. GSK2126458 is prepared in clear bottom polypropylene 384 well plates with consecutive two fold dilutions. 4 μL of these dilutions are added to 105 μL culture media, after mixing the solution, 2 μL of these dilutions are added into each well of the cell plates. The final concentration of DMSO in all wells is 0.15%. Cells are incubated at 37 °C, 5% CO₂ for 72 hours. Following 72 hours of incubation with GSK2126458 each plate is developed and read. CellTiter-Glo reagent is added to assay plates using a volume equivalent to the cell culture volume in the wells. Plates are shaken for approximately two minutes and incubated at room temperature for approximately 30 minutes and chemiluminescent signal is read on the Analyst GT reader. Results are expressed as a percent of the t=0 and plotted against the GSK2126458 concentration. Cell growth inhibition is determined for GSK2126458 by fitting the dose response with a 4 or 6 parameter curve fit using XLfit software and determining the concentration that inhibits 50% of the cell growth (gIC50) with the Y min as the t=0 and Y max as the DMSO control. Value from wells with no cells is subtracted from all samples for background correction.. (Only for Reference)
Animal Research:^[1]	- Collapse Animal Models: Human BT474 tumors implanted in mice. Formulation: GSK2126458 is dissolved in DMSO and then diluted in water. Dosages: ≤300 μg /kg Administration: Administered via p.o. (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	100 mg/mL (197.82 mM)
	Water	Insoluble
	Ethanol	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 2% DMSO+40% PEG 300+2% Tween 80+ddH2O For best results, use promptly after mixing.	4mg/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 Omipalisib (GSK2126458) SDF

Molecular Weight	505.5
Formula	C₂₅H₁₇F₂N₅O₃S
CAS No.	1086062-66-9
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	GSK458
Smiles	COC1=NC=C(C=C1N[S](=O)(=O)C2=CC=C(F)C=C2F)C3=CC=C4N=CC=C(C5=CC=NN=C5)C4=C3

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PI3K Signaling Pathway Map

PI3K Inhibitors with Unique Features

Selective PI3K Inhibitors

CAL-101 (Idelalisib, GS-1101) : p110δ-selective, IC50=2.5 nM.
Selective PI3K Inhibitors

TGX-221 : p110β-specific, IC50=5 nM.
Most Potent PI3K Inhibitor

BEZ235 (NVP-BEZ235, Dactolisib) : p110α/γ/δ/β, IC50=4 nM/5 nM/7 nM/75 nM.
FDA-approved PI3K Inhibitor

CAL-101 (Idelalisib, GS-1101) : Approved by FDA for Relapsed Chronic Lymphocytic Leukemia, Follicular Lymphoma and Small Lymphocytic Lymphoma.
Newest PI3K Inhibitor

VS-5584 (SB2343) ^New : Potent and selective dual PI3K/mTOR inhibitor for mTOR, PI3Kα/β/δ/γ with IC50 of 3.4 nM and 2.6-21 nM, respectively.

Related PI3K Products

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Taselisib (GDC 0032) is a potent, next-generation β isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with K_i of 0.29 nM/0.12 nM/0.97nM, >10 fold selective over PI3Kβ.

Features:A beta isoform-sparing PI3K inhibitor.
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LY294002 is the first synthetic molecule known to inhibit PI3Kα/δ/β with IC50 of 0.5 μM/0.57 μM/0.97 μM, respectively; more stable in solution than Wortmannin, and also blocks autophagosome formation. It not only binds to class I PI3Ks and other PI3K-related kinases, but also to novel targets seemingly unrelated to the PI3K family.
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Idelalisib (CAL-101, GS-1101)

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Omipalisib (GSK2126458)