GSK2126458PI3K/mTOR inhibitor CAS# 1086062-66-9 |
- PP242
Catalog No.:BCC3682
CAS No.:1092351-67-1
- A66
Catalog No.:BCC3715
CAS No.:1166227-08-2
- CAL-101 (Idelalisib, GS-1101)
Catalog No.:BCC1270
CAS No.:870281-82-6
- PIK-294
Catalog No.:BCC4995
CAS No.:900185-02-6
- OSI-027
Catalog No.:BCC4603
CAS No.:936890-98-1
- KU-0063794
Catalog No.:BCC2484
CAS No.:938440-64-3
Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
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. |
Description | GSK2126458 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. | |||||
Targets | p110α | p110δ | p110γ | p110β | mTORC1 | mTORC2 |
IC50 | 0.019 nM(Ki) | 0.024 nM(Ki) | 0.06 nM(Ki) | 0.13 nM(Ki) | 0.18 nM(Ki) | 0.3 nM(Ki) |
GSK2126458 Dilution Calculator
GSK2126458 Molarity Calculator
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. |
Calcutta University
University of Minnesota
University of Maryland School of Medicine
University of Illinois at Chicago
The Ohio State University
University of Zurich
Harvard University
Colorado State University
Auburn University
Yale University
Worcester Polytechnic Institute
Washington State University
Stanford University
University of Leipzig
Universidade da Beira Interior
The Institute of Cancer Research
Heidelberg University
University of Amsterdam
University of Auckland
TsingHua University
The University of Michigan
Miami University
DRURY University
Jilin University
Fudan University
Wuhan University
Sun Yat-sen University
Universite de Paris
Deemed University
Auckland University
The University of Tokyo
Korea University
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.
-
4-Hydroxy-Teriflunomide
Catalog No.:BCC4734
CAS No.:
- Lumichrome
Catalog No.:BCN7083
CAS No.:1086-80-2
- Pyridostatin
Catalog No.:BCC1875
CAS No.:1085412-37-8
- 23S-hydroxy-11,15-dioxo-ganoderic acid DM
Catalog No.:BCN8131
CAS No.:1085273-49-9
- Eupahualin C
Catalog No.:BCN7234
CAS No.:108525-39-9
- Ilexgenin A
Catalog No.:BCC9233
CAS No.:108524-94-3
- Ilexsaponin A
Catalog No.:BCN7867
CAS No.:108524-93-2
- [D-Phe12,Leu14]-Bombesin
Catalog No.:BCC6020
CAS No.:108437-88-3
- [D-Phe12]-Bombesin
Catalog No.:BCC5844
CAS No.:108437-87-2
- FH535
Catalog No.:BCC1573
CAS No.:108409-83-2
- Fuligorubin A
Catalog No.:BCN1837
CAS No.:108343-55-1
- Noradrenaline bitartrate monohydrate
Catalog No.:BCC4810
CAS No.:108341-18-0
- Mizolastine
Catalog No.:BCC4521
CAS No.:108612-45-9
- Purpureaside C
Catalog No.:BCN3865
CAS No.:108648-07-3
- Eupalinolide K
Catalog No.:BCN6199
CAS No.:108657-10-9
- Y 11
Catalog No.:BCC6206
CAS No.:1086639-59-9
- 1-O-Acetyl-6beta-O-Isobutyrylbritannilactone
Catalog No.:BCN1628
CAS No.:1087072-50-1
- Isomeranzin
Catalog No.:BCN5882
CAS No.:1088-17-1
- Nemorubicin
Catalog No.:BCC4151
CAS No.:108852-90-0
- Dendrophenol
Catalog No.:BCC8165
CAS No.:108853-14-1
- Gardenolic acid B
Catalog No.:BCN7140
CAS No.:108864-53-5
- Lupeol 3-hydroxyoctadecanoate
Catalog No.:BCN6686
CAS No.:108885-61-6
- Taccalonolide A
Catalog No.:BCN2737
CAS No.:108885-68-3
- Taccalonolide B
Catalog No.:BCN2743
CAS No.:108885-69-4
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.