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

Abstract

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 eIF4E. Phosphorylation on S209 of eIF4E (p-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 (IC50 of 64 and 86 nM, respectively), inducing dose-dependent inhibition of p-eIF4E with an IC50 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 PBMCs obtained from human healthy volunteers 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 IC50 for p-eIF4E (1.7 µM) for 30 h. While in mouse pharmacodynamic (PD) activity was also shown in tumor, skin, and hair follicles, 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).