Development of an Imidazopyridazine-Based MNK1/2 Inhibitor for the Treatment of Lymphoma

The
mitogen-activated protein kinase-interacting protein kinases
(MNKs) are the only kinases known to phosphorylate eukaryotic translation
initiation factor 4E (eIF4E) at Ser209, which plays a significant
role in cap-dependent translation. Dysregulation of the MNK/eIF4E
axis has been found in various solid tumors and hematological malignancies,
including diffuse large B-cell lymphoma (DLBCL). Herein, structure–activity
relationship studies and docking models determined that 20j exhibits excellent MNK1/2 inhibitory activity, stability, and hERG
safety. 20j exhibits strong and broad antiproliferative
activity against different cancer cell lines, especially GCB-DLBCL
DOHH2. 20j suppresses the phosphorylation of eIF4E in
Hela cells (IC50 = 90.5 nM) and downregulates the phosphorylation
of eIF4E and 4E-BP1 in A549 cells. In vivo studies first revealed
that ibrutinib enhances the antitumor effect of 20j without
side effects in a DOHH2 xenograft model. This study provided a solid
foundation for the future development of a MNK inhibitor for GCB-DLBCL
treatment.