1、ETC-206Cat. No.: HY-112424CAS No.: 1464151-33-4Molecular Formula: CHNOMolecular Weight: 408.45Target: MNKPathway: MAPK/ERK PathwayStorage: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 monthSolvent MNK2, IC50: 86 nMIn Vitro ETC-206 inhibits eIF4E phosphorylation in HeLa cell line with
2、an IC50 of 321 nM. The anti-proliferative effects of ETC-206 are assessed in vitro, using CellTiter-Glo viability assay against 25 hematological cancer cell lines including the K562 cell line that overexpresses eIF4E (K562 o/e eIF4E). The IC50s are 1.71 M, 3.36 M, 3.70 M, 4.81 M, 5.13 M, 5.05 M, 6.7
3、0 M, 9.76 M, and 48.8 M for SU-DHL-6, GK-5, MC 116, P3HR-1, DOHH2, MPC-11, Ramos.2G6.4C10, AHH-1, and K562 o/e eIF4E cells, respectively1.The antitumor effect of ETC-206 is then assessed in a K562 e/o eIF4E mouse xenograft model after oral administration at 25, 50, or 100 mg/kg alone or in combinati
4、on with a 2.5 mg/kg fixed dose of Dasatinib throughout the study. Dasatinib at 2.5 mg/kg elicits a tumor growth inhibition (TGI) of 88% with one tumor-free animal. In In VivoProduct Data Sheet InhibitorsAgonistsScreening Librarieswww.MedChemE1contrast, ETC-206 alone only yields a maximum TGI of 23%
5、at the highest administered dose of 100 mg/kg, which does not impede tumor growth, and is similar to the nontreated animals. ETC-206 with 2.5 mg/kg of Dasatinib not only increases tumor growth inhibition in a dose-dependent manner but, more importantly leads to 2, 5, and 8 out of 8 tumor-free animal
6、s at 25, 50, and 100 mg/kg, respectively. The combination of ETC-206 and Dasatinib inhibits tumor growth at all tested doses, and no weight loss is recorded. Both the combination of ETC-206 and Dasatinib and, on the other hand, the dual MNK1/2 and BCR-ABL1 inhibitors prevent tumor growth in the same
7、 mouse xenograft model. ETC-206 has moderate terminal elimination half-life (t1/2=1.7 h, and 1.77 h for mouse (1 mg/kg, i.v.), mouse (5 mg/kg, p.o.)1.PROTOCOLCell Assay 1 The anti-proliferative effects of ETC-206 are assessed in vitro, using CellTiter-Glo viability assay against 25 hematological can
8、cer cell lines including the K562 cell line that overexpresses eIF4E (K562 o/e eIF4E). The IC50s are in general in the micromolar range1. MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Administration 1Mice1 CD-1 female mice (6-8 weeks old) are w
9、eighed, and those selected for dosing are 242 g. Three mice are randomly grouped per time point. Mice are administered a single dose of 1 mg/kg of ETC-206 via tail vein injection or a single dose of 5 mg/kg of ETC-206 via oral gavage. The volume of injection for intravenous (i.v.) and oral (p.o.) ad
10、ministration is 4 mL/kg and 8 mL/kg, respectively1. MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Yang H, et al. Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia. J Med Chem. 2018 May 24;61(10):4348-4369.Caution: Product has not been fully validated for medical applications. For research use only.Tel: 609-228-6898 Fax: 609-228-5909 E-mail: techMedChemEAddress: 1 Deer Park Dr, Suite Q, Monmouth Junction, NJ 08852, USAwww.MedChemE2
