ETC-206 is a selective inhibitor of MNK1 and MNK2 (IC50s: 64 nM and 86 nM).

MNK2:86 nM, MNK1:64 nM

ETC-206's anti-proliferative effects were evaluated in vitro across 25 hematological cancer cell lines, including K562 cells overexpressing eIF4E (K562 o/e eIF4E), through a CellTiter-Glo viability assay. The compound efficiently inhibited eIF4E phosphorylation in the HeLa cell line, showing an IC50 of 321 nM. Its IC50 values across other cell lines, including SU-DHL-6, GK-5, MC 116, P3HR-1, DOHH2, MPC-11, Ramos.2G6.4C10, AHH-1, and K562 o/e eIF4E, ranged from 1.71 μM to 48.8 μM, demonstrating varying degrees of efficacy against these cancer cells.

The antitumor efficacy of ETC-206 was evaluated in a K562 e/o eIF4E mouse xenograft model via oral doses of 25, 50, or 100 mg/kg, either as a standalone treatment or in combination with a consistent 2.5 mg/kg dose of Dasatinib throughout the study. Remarkably, when combined with Dasatinib, ETC-206 not only enhanced tumor growth inhibition in a dose-responsive manner but also resulted in tumor clearance in 2, 5, and 8 out of 8 mice at doses of 25, 50, and 100 mg/kg, respectively. This combination effectively suppressed tumor growth across all tested concentrations without causing weight loss in the animals. Independently, ETC-206’s maximum tumor growth inhibition (TGI) was recorded at 23% with the highest dose of 100 mg/kg, a result that was unable to significantly halt tumor progression, aligning closely with outcomes observed in untreated controls. Moreover, both the combination of ETC-206 and Dasatinib and the integration of dual MNK1/2 and BCR-ABL1 inhibitors demonstrated preventative effects on tumor development within this mouse xenograft model. Additionally, ETC-206 displayed a moderate terminal elimination half-life (t1/2=1.7 h, and 1.77 h for mouse (1 mg/kg, intravenous [i.v.]), mouse (5 mg/kg, oral [p.o.])).