GSK2636771

Names

[ Name ]:
GSK2636771

[Synonym ]:
GSK2636771
UNII-DW94IAT0LS
cc-414
1H-Benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-
CS-0747
2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid
QCR-187
2-Methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid
GSK-2636771

Biological Activity

[Description]:

GSK2636771 is a potent, selective and oral inhibitor of PI3Kβ with a Ki of 0.89 nM and an IC50 of 5.2 nM, showing 900-fold selectivity over p110α and p110γ, and 10-fold selectivity over p110δ isoforms.

[Related Catalog]:

Research Areas >> Cancer

[Target]

p110β

[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].

[Cell Assay]

Cells are plated in 96-well microtiter plates at densities ranging from 1,500 to 15,000 cells/well, optimized for untreated control cells to be 80-90% confluent at the endpoint of the experiment. After 24 h, cells are treated with serial dilutions (100 pM to 10 µM) of the PI3K pathway inhibitors GDC-0941, A66, TGX-221, GSK2636771, AZD6482, Temsirolimus, AZD8055, PF-04691502, and of the MAPK pathway inhibitors AZD6244, PD0325901, AZD628, and PLX4032. Cell viability is assessed after 72 h of treatment by incubation with CellTiter Blue for 1.5 h. The drug concentration required for survival of 50% of cells relative to untreated cells is determined using GraphPad Prism version 5.0 d. Cell lines that fail to achieve the SF50 to a given drug are nominally assigned as the highest concentration screened (10 µM). At least three independent experiments in triplicate per cell line/targeted drug are performed. Association between a mutation and response to a targeted agent is determined using a Fisher’s exact test, and a two-tailed P value.

[References]

[1]. Weigelt B, et al. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013, 19(13), 3533-3544.

[2]. Hosford SR, et al. Combined inhibition of both p110α and p110β isoforms of phosphatidylinositol 3-kinase is required for sustained therapeutic effect in PTEN-deficient, ER+ breast cancer. Clin Cancer Res. 2016 Nov 30

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
641.3±55.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₂H₂₂F₃N₃O₃

[ Molecular Weight ]:
433.424

[ Flash Point ]:
341.7±31.5 °C

[ Exact Mass ]:
433.161316

[ PSA ]:
67.59000

[ LogP ]:
3.61

[ Vapour Pressure ]:
0.0±2.0 mmHg at 25°C

[ Index of Refraction ]:
1.606

Safety Information

[ Hazard Codes ]:
Xi