c-Kit-IN-3-DataSheet-生命科學試劑-MedChemExpresss

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEc-Kit-IN-3Cat. No.: HY-128704CAS No.: 2363169-01-9分式: CHClFNO分量: 516.9作靶點: c-Kit作通路: Protein Tyrosine Kinase/RTK儲存式: Please store the product under the recommended conditions inthe COA.BIOLOGICAL ACTIVITY物活性 c-Kit-IN-3 (compound

2、 18)種有效的 c-KIT 激酶抑制劑，對 BaF3-tel-c-KIT (IC50 為 4 nM) 和泛的耐藥性突變體 (對 BaF3-tel-c-KIT-T670I 的 IC50 為 8 nM)，具有更的物利度。體外研究c-Kit-IN-3 (compound 18; 0.01-1 M; 2 hours; GIST-T1, GIST-T1-T670I, and GIST-5R cells) treatment blocksthe autophosphorylation of c-KIT pY703, pY719, and pY823 in GIST-T1, GIST-T1-T670I,

3、and GIST-5R,respectively, cells at a concentration of 30 nM and also remarkably inhibits the downstream signalingmediators pAKT (T308/S473), pS6 (S235/236), and pERK (T202/204) (EC50 less than 100 nM). c-Kit-IN-3also significantly affects the phosphorylation of cKIT pY703, pY719, and pY823 and downs

4、tream mediators(EC50 less than 100 nM). c-Kit-IN-3 strongly inhibits the phosphorylation of STAT3 in GIST-T1-T670I andGIST-5R cells but moderately in GIST-T1 cells 1.c-Kit-IN-3 (compound 18; 0.01-1 M; 24 hours; GIST-T1, GIST-T1-T670I, and GIST-5R cells) treatmentinduces dose-dependent cell apoptotic

5、 death (by examining the cleaved PARP and cleaved caspase 3) 1.c-Kit-IN-3 (compound 18; 0.01-1 M; 24 hours; GIST-T1, GIST-T1-T670I, and GIST-5R cells) treatmentarrests the cell cycle into the G0/G1 phase in all of these three cell lines 1.c-Kit-IN-3 (compound 18; 0.1-10 M; 6 days; primary GIST patie

6、nt cells) exhibits dose-dependentantiproliferative effects 1.Western Blot Analysis 1Cell Line: GIST-T1, GIST-T1-T670I, and GIST-5R cellsConcentration: 0.01 M, 0.03 M, 0.1 M, 0.3 M, 1 MIncubation Time: 2 hours1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEResult: Blocked the autophosphorylation of

7、c-KIT pY703, pY719, and pY823 in GIST-T1, GIST-T1-T670I, and GIST-5R, respectively, cells at a concentration of 30 nM and alsoremarkably inhibited the downstream signaling mediators pAKT (T308/S473), pS6(S235/236), and pERK (T202/204) (EC50 less than 100 nM). Also significantly affectedthe phosphory

8、lation of cKIT pY703, pY719, and pY823 and downstream mediators(EC50 less than 100 nM). Strongly inhibited the phosphorylation of STAT3 in GIST-T1-T670I and GIST-5R cells but moderately in GIST-T1 cells.Apoptosis Analysis 1Cell Line: GIST-T1, GIST-T1-T670I, and GIST-5R cellsConcentration: 0.01 M, 0.

9、03 M, 0.1 M, 0.3 M, 1 MIncubation Time: 24 hoursResult: Induced dose-dependent cell apoptotic death.Cell Cytotoxicity Assay 1Cell Line: GIST-T1, GIST-T1-T670I, and GIST-5R cellsConcentration: 0.01 M, 0.03 M, 0.1 M, 0.3 M, 1 MIncubation Time: 24 hoursResult: Arrested the cell cycle into the G0/G1 pha

10、se in all of these three cell lines.Cell Proliferation Assay 1Cell Line: Primary GIST patient cellsConcentration: 0.1 M, 0.3 M, 1 M, 3 M, 10 MIncubation Time: 6 daysResult: Inhibition of the proliferation of primary GIST patient cells.體內(nèi)研究c-Kit-IN-3 (compound 18; 40-100 mg/kg; oral gavage; daily; fo

11、r 11 days; for 4 weeks; female BALB/C-numice) treatment dose dependently inhibits the BaF3-tel-c-KIT-T670I tumor progression and exhibited almost100% TGI (tumor growth inhibition) at a dosage of 100 mg/kg/day. And do not affect the animal weights 1.Animal Model: Female BALB/C-nu mice bearing establi

12、shed BaF3-tel-c-KIT-T670I tumor xenografts 1Dosage: 40 mg/kg, 100 mg/kgAdministration: Oral gavage; daily; for 11 days2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEResult: Dose dependently inhibited the BaF3-tel-c-KIT-T670I tumor progression and exhibitedalmost 100% TGI (tumor growth inhibition)

13、at a dosage of 100 mg/kg/day.REFERENCES1. Wu Y, et al. Discovery of 2-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(4-(6,7-dimethoxyquinolin-4-yl)oxy)phenyl)acetamide (CHMFL-KIT-64) as a Novel Orally Available Potent Inhibitor against Broad-Spectrum Mutants of c-KIT Kinase for Gastrointestinal Stromal Tumors. J MedChem. 2019 Jul 11;62(13):6083-6101.McePd