GSK2636771PIK3 inhibitor CAS# 1372540-25-4 |
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Quality Control & MSDS
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| Cas No. | 1372540-25-4 | SDF | Download SDF |
| PubChem ID | 56949517 | Appearance | Powder |
| Formula | C22H22F3N3O3 | M.Wt | 433.42 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 25 mg/mL (57.68 mM; Need ultrasonic) | ||
| Chemical Name | 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid | ||
| SMILES | CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C2C=C(C=C3C(=O)O)N4CCOCC4)C | ||
| Standard InChIKey | XTKLTGBKIDQGQL-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C22H22F3N3O3/c1-13-15(4-3-5-18(13)22(23,24)25)12-28-14(2)26-20-17(21(29)30)10-16(11-19(20)28)27-6-8-31-9-7-27/h3-5,10-11H,6-9,12H2,1-2H3,(H,29,30) | ||
| 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. |
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| 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. |
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| 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 | GSK2636771 is a potent, selective and orally bioavailable PI3Kβ inhibitor, sensitive to PTEN null cell lines.In Vitro:GSK2636771 treatment causes cell viability significantly more decreased in the control cells (p110β-reliant PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines) than in PTEN-mutant and PTEN wild-type EEC cells. Inhibition of p110β by GSK2636771 or AZD6482 leads to a marked decrease of AKT phosphorylation only in the control prostate and breast cancer cell lines, whereas only marginal effects on AKT activation are observed in EEC cells[1].In Vivo:GSK2636771 is a p110β inhibitor, and the p110β primes cells for response to growth factor stimulation. While p110β inhibition suppresses cell and tumor growth, dual targeting of p110α/β enhances apoptosis and provides sustained tumor response in mice model[2]. References: | |||||
GSK2636771 Dilution Calculator
GSK2636771 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.3072 mL | 11.5362 mL | 23.0723 mL | 46.1446 mL | 57.6808 mL |
| 5 mM | 0.4614 mL | 2.3072 mL | 4.6145 mL | 9.2289 mL | 11.5362 mL |
| 10 mM | 0.2307 mL | 1.1536 mL | 2.3072 mL | 4.6145 mL | 5.7681 mL |
| 50 mM | 0.0461 mL | 0.2307 mL | 0.4614 mL | 0.9229 mL | 1.1536 mL |
| 100 mM | 0.0231 mL | 0.1154 mL | 0.2307 mL | 0.4614 mL | 0.5768 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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GSK2636771 is a p110β isoform-specific inhibitor of PIK3 with SF50 more than 1 μM [1].
PI3K (phosphatidylinositol 3-kinase) has 4 catalytic subunits: p110α, β, δ, γ，and δ. PI3K /AKT and related pathways play important roles in cellular growth and survival via internalizing the effects of external growth factors and membrane tyrosine kinases. [2, 3]. Many studies have shown that PI3K is over activated in a variety of cancer cells and inhibition of this pathway have been focused for cancer patients [4].
GSK2636771 is a selective PI3K inhibitor with targeting p110βand has different with the reported GDC-0941 which inhibits all class I PI3K isoforms. In breast cancer cell lines, treatment with GSK2636771 could significantly decrease the phosphorylation of AKT thus inhibits the cell viability. For EEC cell lines with PTEN-mutant, p110β inhibitor GSK2636771 should only combine with p110α selective inhibitor A66 to decrease cell viability [1].
References:
1.Weigelt, B., et al., PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res, 2013. 19(13): p. 3533-44.
2.Costa, C., et al., Measurement of PIP Levels Reveals an Unexpected Role for p110beta in Early Adaptive Responses to p110alpha-Specific Inhibitors in Luminal Breast Cancer. Cancer Cell, 2014. 24(14): p. 00458-9.
3.Schwartz, S., et al., Feedback Suppression of PI3Kalpha Signaling in PTEN-Mutated Tumors Is Relieved by Selective Inhibition of PI3Kbeta. Cancer Cell, 2014. 24(14): p. 00459-0.
4.Slomovitz, B.M. and R.L. Coleman, The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. Clin Cancer Res, 2012. 18(21): p. 5856-64.
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A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors.[Pubmed:28645941]
Clin Cancer Res. 2017 Oct 1;23(19):5981-5992.
Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110beta could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kbeta.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (>/=24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (>/=34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981-92. (c)2017 AACR.
