| Identification | Back Directory | [Name]
GSK2636771 | [CAS]
1372540-25-4 | [Synonyms]
CS-357
GSK2636771
GSK 2636771B
GSK2636771cas
GSK2636771 USP/EP/BP
GSK2636771/GSK-2636771
GSK 2636771 dihydrochloride
PI3Kβ-selective inhibitor GS2636771
2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic
2-METHYL-1-[[2-METHYL-3-(TRIFLUOROMETHYL)PHENYL]METHYL]-6-MORPHOLIN-4-YLBENZIMIDAZOLE-4-CARBOXYLIC ACID
2-Methyl-1-[[2-Methyl-3-(trifluoroMethyl)phenyl]Methyl]-6-(4-Morpholinyl)-1H-benziMidazole-4-carboxylic acid
1H-Benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-
2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(morpholin-4-yl)-1H-1,3-benzodiazole-4-carboxylic acid
2-Methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid GSK2636771 | [Molecular Formula]
C22H22F3N3O3 | [MDL Number]
MFCD22417098 | [MOL File]
1372540-25-4.mol | [Molecular Weight]
433.424 |
| Chemical Properties | Back Directory | [Melting point ]
>225°C (dec.) | [Boiling point ]
641.3±55.0 °C(Predicted) | [density ]
1.38 | [storage temp. ]
-20°C Freezer | [solubility ]
DMSO (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
-2.70±0.30(Predicted) | [color ]
Pale Yellow | [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) | [InChIKey]
XTKLTGBKIDQGQL-UHFFFAOYSA-N | [SMILES]
C1(C)N(CC2=CC=CC(C(F)(F)F)=C2C)C2=CC(N3CCOCC3)=CC(C(O)=O)=C2N=1 |
| Hazard Information | Back Directory | [Description]
GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ with an apparent Ki value of 0.89 nmol/L (IC50 = 5.2 nmol/L), >900-fold selectivity over p110α and p110γ, and >10-fold selectivity over p110δ isoforms, while sparing other PI3K superfamily kinases[1-2]. | [Uses]
GSK2636771 is a potent, orally bioavailable, PI3Kβ-selective inhibitor, sensitive to PTEN null cell lines. | [Synthesis]
2-Methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate (180 mg, 0.4 mmol) was used as a starting material and dissolved in THF (10 mL). To this solution, 2N LiOH aqueous solution (1.2 mL) was added, followed by stirring the reaction at 50 °C for 1 hour. The progress of the reaction was monitored by TLC and after confirming complete consumption of the feedstock, the reaction mixture was cooled to room temperature. THF was removed under reduced pressure and the mixture was subsequently acidified by adjusting the pH to 3. The resulting suspension was filtered and the filter cake was washed with water (10 mL) to give the final white solid product 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylic acid (152 mg, yield). The product was characterized by 1H NMR (300 MHz, DMSO-d6): δ 2.46 (s, 3H), 2.54 (s, 3H), 3.10 (t, 4H, J = 4.8 Hz), 3.73 (t, 4H, J = 4.8 Hz), 5.63 (s, 2H), 6.37 (d, 1H, J = 7.8 Hz), 7.26 (t, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 2.4 Hz), 7.44 (d, 1H, J = 2.4 Hz), 7.62 (d, 1H, J = 7.8 Hz); LC-MS: m/e = 434 [M + 1]+. | [in vitro]
GSK-2636771 shows selectively inhibitory activity in PTEN null cell lines (human prostate adenocarcinoma PC-3 and breast cancer HCC70) with EC50 of 36 nM and 72 nM, respectively. GSK2636771 significantly decreases cell viability in p110β-reliant PTEN-deficient PC3 prostate and BT549 and HCC70 breast cancer cell lines. It leads to a marked decrease of AKT phosphorylation only in the control prostate and breast cancer cell lines.
| [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]. | [IC 50]
PI3Kβ: 0.89 nM (Ki); PI3Kβ: 5.2 nM (IC50) | [References]
[1] Mateo, Joaquin , et al. "A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors." Clinical Cancer Research (2017):clincanres.0725.2017.
[2] Sarker, Debashis , et al. "A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer." Clinical Cancer Research 27.19(2021):5248-5257.
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