X-376 - ALK and MET 抑制劑 - 生命科學(xué)試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEX-376Cat. No.: HY-16590CAS No.: 1365267-27-1分式: CHClFNO分量: 547.41作靶點(diǎn): ALK; c-Met/HGFR作通路: Protein Tyrosine Kinase/RTK儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 37 mg/mL (67.59 mM)* mea

2、ns soluble, but saturation unknown.Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 1.8268 mL 9.1339 mL 18.2678 mL5 mM 0.3654 mL 1.8268 mL 3.6536 mL10 mM 0.1827 mL 0.9134 mL 1.8268 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 X-376種有效的雙重 的 ALK/MET 抑制劑，IC50 分別為 0.61 nM 和 0.6

3、9 nM。IC50 & Target ALK MET0.61 nM (IC50) 0.69 nM (IC50)體外研究The ability of X-376 to inhibit the growth of different cancer cell lines harboring ALK fusions or point mutations1/2 Master of Small Molecules 您邊的抑制劑師www.MedChemEis tested. X-376 is potent in H3122 lung cancer cells harboring EML4-ALK E13;A

4、20 (IC50: 77 nM). X-376 isalso potent in H2228 lung cancer cells harboring EML4-ALK E6a/b; A20 (IC50: 57 nM). Furthermore, X-376is potent in SUDHL-1 lymphoma cells harboring NPM-ALK (IC50: 32 nM). X-376 also inhibits SY5Yneuroblastoma cells harboring ALK F1174L, MKN-45 gastric carcinoma cells harbor

5、ing MET dependent,HepG2 cells and PC-9 lung cancer cell lines harboring EGFR exon 19 del with IC50s of 142 nM, 150 nM,15.137 M and 3.062 M, respectively 1.體內(nèi)研究 The effects of X-376 in vivo against H3122 xenografts are examined. A pharmacokinetic study reveals that X-376 shows substantial bioavailabi

6、lity and moderate half-lives in vivo. Nude mice harboring H3122 xenograftsare treated with X-376 at 50 mg/kg bid. X-376 significantly delays the growth of tumors compared to vehiclealone. In the xenograft experiments, X-376 appears well-tolerated in vivo. Mouse weight is unaffected by X-376 treatmen

7、t. Drug-treated mice appear healthy and do not display any signs of compound related toxicity.To further assess potential side effects of X-376, additional systemic toxicity and toxico-kinetic studies areperformed in Sprague Dawley (SD) rats. Following 10 days of repeated oral administration of X-37

8、6 at 25,50, 100 mg/kg in SD rats, all animals survive to study termination. The no significant toxicity (NST) levels aredetermined to be 50 mg/kg for X-376. At NST levels, X-376 achieves an AUC of 41 Mhr and a Cmax of5.04 M 1.PROTOCOLCell Assay 1 For viability experiments, cells are seeded in 96-wel

9、l plates at 25%-33% confluency and exposed to drugs.The human lung adenocarcinoma cell lines H3122 and H2228 are treated with X-376 (10, 30, 100, 300 and1000 nM). SUDHL-1 lymphoma cells are treated with X-376 (5, 10, 30, 100 and 300 nM). SY5Yneuroblastoma cells are treated with X-376 (30, 100, 300 a

10、nd 1000 nM). At 72 hours post X-376 addition,Cell Titer Blue Reagent is added and fluorescence is measured on a Spectramax spectrophotometer. Allexperimental points are set up in hextuplicate replicates and are performed at least two independent times.IC50s are calculated using GraphPad Prism versio

11、n 5 for Windows. The curves are fit using a nonlinearregression model with a log (inhibitor) vs. response formula 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 1Administration 1 Nude mice (nu/nu) are injected with H3122 cells. Once tumor

12、s reach an average volume of 450 mm3, a totalof 27 athymic mice harboring H3122 tumors are randomized and dosed via oral gavage with 50 mg/kg X-376or the control vehicle. Two, five, and fifteen hours after the single treatment (3 tumors/timepoint/group), miceare sacrificed and serum is collected for

13、 assessment of drug concentration using an LC-MS basedbioanalytical method.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Lovly CM, et al. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinaseinhibitors. Cancer Res.2011 Jul 15;71(14):4920-31.McePdfHeight2/2 Master of Small Molecules 您邊的抑制劑師ww