c-Kit-IN-3-L-tartrate-DataSheet-生命科学试剂-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEc-Kit-IN-3 L-tartrateCat. No.: HY-128704A6分式: CHClFNO分量: 666.98作靶点: c-Kit作通路: Protein Tyrosine Kinase/RTK储存式: Please store the product under the recommended conditions inthe COA.BIOLOGICAL ACTIVITY物活性 c-Kit-IN-3 L-tartrate (Comp

2、ound 18)种有效的 c-KIT 激酶抑制剂，对 c-KIT wt 和 c-KIT T670I 的 IC50 分别为 4 nM 和 8 nM。c-Kit-IN-3 L-tartrate 对近膜结构域中的多数功能获得性突变，ATP 结合袋中的抗药性突变以及激活环显出强的效。IC50 & Target IC50: 4 nM (c-KIT w) and 8 nM (c-KIT T670I) 1体外研究c-Kit-IN-3 L-tartrate (Compound 18; 0.1-10 M; 6 days; primary GIST patient cells) exhibits dose-dep

3、endentantiproliferative effects 1.c-Kit-IN-3 L-tartrate (0.01-1 M; 24 hours; GIST-T1, GIST-T1-T670I, and GIST-5Rcells) treatment induces dose-dependent cell apoptotic death (by examining the cleaved PARP and cleavedcaspase 3) 1.c-Kit-IN-3 L-tartrate (0.01-1 M; 24 hours; GIST-T1, GIST-T1-T670I, and G

4、IST-5R cells) treatment arreststhe cell cycle into the G0/G1 phase in all of these three cell lines 1.c-Kit-IN-3 L-tartrate (0-1 M; 24 hours) blocks the autophosphorylation of c-KIT pY703, pY719, and pY823 inGIST-T1, GIST-T1-T670I, and GIST-5R, respectively, cells at a concentration of 30 nM and inh

5、ibits thedownstream signaling mediators pAKT (T308/S473), pS6 (S235/236), and pERK (T202/204) 1.c-Kit-IN-3 L-tartrate potently inhibits the activity of CSF1R (IC50: 18 nM), PDGFR (IC50: 25 nM), RET(IC50: 34 nM), and it relatively less potently inhibits DDR1 (IC50: 135 nM), FLT4 (IC50: 121 nM), and P

6、DGFR (IC50: 97 nM) 1.c-Kit-IN-3 L-tartrate (0.006 M-1.37 M) potently inhibits the growth of c-KIT-dependent GIST cancer cells,such as GIST-T1 (IC50: 0.006 M); GIST-882 (IC50: 0.013 M); GIST-T1-T670I (IC50: 0.011 M); GIST-5R(IC50: 0.073 M); GIST-48B (IC50: 1.37 M), respectively 1.Cell Proliferation A

7、ssay 11/3 Master of Small Molecules 您边的抑制剂师www.MedChemECell 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.Cell Cycle Analysis 1Cell Line: GIST-T1, GIST-T1-T670I, and GIST-5R cell

8、sConcentration: 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 phase in all of these three cell lines.Apoptosis 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: 24

9、hoursResult: Induced dose-dependent cells apoptotic death.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: 24 hoursResult: Decreased the autophosphorylation of c-KIT pY703, pY719, and pY823 in GIST-T1,GIST-T1-

10、T670I, and GIST-5R cells, respectively.体内研究c-Kit-IN-3 L-tartrate (Compound 18; oral gavage; 20-100 mg/kg/day; for 11 days; female BALB/C-nu mice)treatment dose dependently inhibits the tumor progression 1.c-Kit-IN-3 L-tartrate (1 mg/kg (iv for mice, rats, dog); 10 mg/kg (p.o. for mice, rats ) and 5

11、mg/kg (p.o. fordog) has T1/2 of 4.5 h, 6.4 h, 19.4 h for mice, rats and dogs, respectively. And it possesses acceptablebioavailability in mice (F = 43%), rats (F = 50%), and dogs (F = 81%) 1.Animal Model: Female BALB/C-nu mice 1Dosage: 20 mg/kg, 40 mg/kg, 80 mg/kg, 100 mg/kg2/3 Master of Small Molec

12、ules 您边的抑制剂师www.MedChemEAdministration: Oral gavage; daily; for 11 daysResult: Dose dependently inhibited the tumor progression.Animal Model: Mice, Sprague Dawley Rats, and Beagle Dogs 1Dosage: 1 mg/kg (iv for mice, rats, dog); 10 mg/kg (p.o. for mice, rats ) and 5 mg/kg (p.o. for dog)(Pharmacokinet

13、ic Analysis)Administration: Iv or p.o.Result: Had T1/2 of 4.5 h, 6.4 h, 19.4 h for mice, rats and dogs, respectively. And it possessedacceptable bioavailability in mice (F = 43%), rats (F = 50%), and dogs (F = 81%).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-