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

Author(s): Bong Hwa Gan, Lay Hoon Lee, Reika Takeda, Maryam Yasin, Vincenzo Teneggi, Kantharaj Ethirajulu, Pauline Yeo, Dhananjay Umrani, Vishal Pendharkar, Darren Wan Teck Lim, Greg Li, Qingshu Lu, Yang Cao, Ranjani Nellore, Stephanie Blanchard, Hannes Hentze, Veronica Novotny-Diermayr

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).