Pharmacodynamic evaluation of AUM001/tinodasertib, an oral inhibitor of mitogen-activated protein kinase (MAPK)-interacting protein kinase 1, 2 (MNK1/2) in preclinical models and tissues from a Phase 1 clinical study

Mitogen-activated protein kinase (MAPK) interacting kinase (MNK) inhibitors affect cap-dependent mRNA translation by blocking the phosphorylation of RNA-binding proteins such as the eukaryotic initiation factor 4E (eIF4E). Phosphorylation on serine (Ser) 209 of eIF4E causes hyperactivation and dysregulation of mRNA translation, which is a hallmark of numerous malignancies. AUM001/Tinodasertib (ETC-206) is a selective and potent oral kinase inhibitor of MNK1 and MNK2 (IC ₅₀ of 64 and 86 nM, respectively), inducing dose-dependent inhibition of eIF4E phosphorylation on Ser209 (p-eIF4E) with an IC ₅₀ of 0.8 µM in K562-eIF4E cells. In mice, single oral doses of ∼12.5 mg/kg led to rapid (1-2 h post-dose) ∼70% inhibition of p-eIF4E in different normal or tumor tissues at a plasma concentration of 8.6 μM. However, in peripheral blood mononuclear cells (PBMCs), obtained from human healthy volunteers (HVs) in a Ph1 study, single oral doses of 10 or 20 mg ETC-206 did not show inhibitory activity up to 12 h post-dose, instead ETC-206 caused a statistically significant (p=0.0037) p-eIF4E inhibition in PBMCs of 24% at 24 h post-dose with 10 mg, and an inhibition of ≥27 % up to 52% was seen in 11/14 subjects in the 20 mg group where ETC-206 plasma concentrations remained above the IC ₅₀ for p-eIF4E (1.7 µM) for 30 h. While in mouse pharmacodynamic (PD) activity was also shown in tumor, skin, and hair follicles (HFs), in human tissues, PBMCs showed a trend for delayed PD inhibition and skin was not a suitable surrogate. Analysis of pharmacokinetic (PK) and PD relationships shown herein demonstrate excellent pharmaceutical properties of ETC-206 which has now advanced to Ph2 clinical trials ( NCT05462236 ).