GSK2126458

PI3K/mTOR inhibitor CAS# 1086062-66-9

GSK2126458

2D Structure

Catalog No. BCC3884----Order now to get a substantial discount!

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3D structure

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GSK2126458

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Chemical Properties of GSK2126458

Cas No. 1086062-66-9 SDF Download SDF
PubChem ID 25167777 Appearance Powder
Formula C25H17F2N5O3S M.Wt 505.5
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Omipalisib
Solubility DMSO : 50 mg/mL (98.91 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 2,4-difluoro-N-[2-methoxy-5-(4-pyridazin-4-ylquinolin-6-yl)pyridin-3-yl]benzenesulfonamide
SMILES COC1=C(C=C(C=N1)C2=CC3=C(C=CN=C3C=C2)C4=CN=NC=C4)NS(=O)(=O)C5=C(C=C(C=C5)F)F
Standard InChIKey CGBJSGAELGCMKE-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H17F2N5O3S/c1-35-25-23(32-36(33,34)24-5-3-18(26)12-21(24)27)11-17(13-29-25)15-2-4-22-20(10-15)19(7-8-28-22)16-6-9-30-31-14-16/h2-14,32H,1H3
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of GSK2126458

DescriptionGSK2126458 is a highly selective and potent inhibitor of p110α/β/δ/γ, mTORC1/2 with Ki values of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM, respectively.
Targetsp110αp110δp110γp110βmTORC1mTORC2
IC500.019 nM(Ki)0.024 nM(Ki)0.06 nM(Ki)0.13 nM(Ki)0.18 nM(Ki)0.3 nM(Ki)

Protocol

Kinase Assay [1]
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). PI3 Kinase 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 2.5 μL 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 2.5 μL 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 2.5 μL 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 330 nm excitation and dual emission detection at 620 nm (Eu) and 665 nm (APC).

Cell Assay [1]
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..

References:
[1]. Knight SD, et al. Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med. Chem. Lett. 2010, 1 (1), 39-43. [2]. Greger JG, et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther. 2012 Apr;11(4):909-20. [3]. Kim HG, et al. Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol. 2013 Oct 18;8(10):2145-50.

GSK2126458 Dilution Calculator

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GSK2126458 Molarity Calculator

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Preparing Stock Solutions of GSK2126458

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9782 mL 9.8912 mL 19.7824 mL 39.5648 mL 49.456 mL
5 mM 0.3956 mL 1.9782 mL 3.9565 mL 7.913 mL 9.8912 mL
10 mM 0.1978 mL 0.9891 mL 1.9782 mL 3.9565 mL 4.9456 mL
50 mM 0.0396 mL 0.1978 mL 0.3956 mL 0.7913 mL 0.9891 mL
100 mM 0.0198 mL 0.0989 mL 0.1978 mL 0.3956 mL 0.4946 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on GSK2126458

GSK2126458 is an inhibitor of PI3K/mTOR with Ki value of 19 pM for PI3K [1].
PI3K (phosphoinositide 3-kinase) plays an important role in regulating cell growth and transformation, and mTOR (mammalian target of rapamycin) which works as a class IV PI3K protein kinase, is also a crucial regulator of cell growth [2]. It has been shown that up-regulation of PI3K/mTOR (phosphatidylinositol-3' kinase/mammalian target of rapamycin) signaling is widespread in carcinoma which may be worked as a biomarker used in clinic [3].
GSK2126458 is a highly potent inhibitor of PI3K/mTOR. When subjected to colorectal cancer cell lines, GSK2126458 could potentiate the cells antiproliferative activity via combining with DDR1-IN-1[4]. In BT474 breast cancer lines, treated with GSK2126458 could be the arrest of G1 cell cycle and thus inhibit cell proliferation [5]. GSK2126458 also could improve the sensitivity of NPC cells to radiation and suppress tumor progression [1].  
In a 5-8F xenograft model with NPC, treated the mouse with GSK2126458 combining of IR significantly inhibited the tumor growth [1]. In mice injected with cancer cells from melanoma patient resisted to the combination of divergent and trametinib, GSK2126458 combined with dabrafenib, trametinib treatment resulted in sustained inhibition of tumor growth[3].
GSK2126458 may play a significant role in regulating autophagy [6].
References:
1.Liu, T., et al., Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther, 2014. 12.
2.Simpson, D.R., L.K. Mell, and E.E. Cohen, Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck: Oral Oncol. 2014 Dec 17. pii: S1368-8375(14)00351-0. doi: 10.1016/j.oraloncology.2014.11.012.
3.Villanueva, J., et al., Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep, 2013. 4(6): p. 1090-9.
4.Kim, H.G., et al., Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. ACS Chem Biol, 2013. 8(10): p. 2145-50.
5.Knight, S.D., et al., Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin. ACS Med Chem Lett, 2010. 1(1): p. 39-43.
6.Zhang, Y., et al., Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways. Mol Med Rep, 2014. 9(1): p. 83-90.

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References on GSK2126458

First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies.[Pubmed:26603258]

Clin Cancer Res. 2016 Apr 15;22(8):1932-9.

PURPOSE: GSK2126458 (GSK458) is a potent inhibitor of PI3K (alpha, beta, gamma, and delta), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. RESULTS: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade >/=3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant). CONCLUSIONS: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.

Liquid chromatography-tandem mass spectrometric assay for the PI3K/mTOR inhibitor GSK2126458 in mouse plasma and tumor homogenate.[Pubmed:25659532]

J Pharm Biomed Anal. 2015 Mar 25;107:403-8.

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for GSK2126458, a dual PI3K/mTOR inhibitor, was developed and validated. Plasma and tumor homogenate samples were pre-treated using protein precipitation with acetonitrile containing dabrafenib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was completely validated for plasma in a 4-4000 ng/ml calibration range with r(2)=0.9996+/-0.0003 using double logarithmic calibration (n=5). Within-run precisions (n=6) were 2.0-5.3% and between-run (3 runs; n=18) precisions 2.7-5.8%. Accuracies were between 101 and 105% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully applied to determine plasma and tumor drug levels after oral administration of GSK2126458 to mice with AMC711T neuroblastoma xenografts.

Factors Influencing the Central Nervous System Distribution of a Novel Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor GSK2126458: Implications for Overcoming Resistance with Combination Therapy for Melanoma Brain Metastases.[Pubmed:26604245]

J Pharmacol Exp Ther. 2016 Feb;356(2):251-9.

Small molecule inhibitors targeting the mitogen-activated protein kinase pathway (Braf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) have had success in extending survival for patients with metastatic melanoma. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. Recent reports have shown that GSK2126458 [2,4-difluoro-N-(2-methoxy-5-(4-(pyridazin-4-yl)quinolin-6-yl)pyridin-3-yl) benzenesulfonamide], a dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor, can overcome acquired resistance to Braf and mitogen-activated protein kinase kinase inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood-brain barrier. The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), two dominant active efflux transporters in the blood-brain barrier. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared with the wild type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome mitogen-activated protein kinase inhibitor resistance, all had limited brain distribution. Coadministration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors but was ineffective in intracranial melanoma. These results show that P-gp and Bcrp are involved in limiting the brain distribution of GSK2126458 and provide a rationale for the lack of efficacy of GSK2126458 in the orthotopic PDX model.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.[Pubmed:27450049]

Invest New Drugs. 2016 Dec;34(6):740-749.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Description

Omipalisib (GSK2126458) is a highly selective and potent inhibitor of PI3K with Kis of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM for p110α/β/δ/γ, mTORC1/2, respectively.

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