Discovery of D25, a Potent and Selective MNK Inhibitor for Sepsis-Associated Acute Spleen Injury

Mitogen-activated protein kinase-interacting protein
kinases (MNKs)
and phosphorylate eukaryotic initiation factor 4E (p-eIF4E) play a
critical role in regulating mRNA translation and protein synthesis
associated with the development of cancer, metabolism, and inflammation.
This study undertakes the modification of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine structure, leading to the discovery
of 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (D25) as a potent
and selective MNK inhibitor. D25 demonstrated inhibitory activity,
with IC50 values of 120.6 nM for MNK1 and 134.7 nM for
MNK2, showing exceptional selectivity. D25 inhibited the expression
of pro-inflammation cytokines in RAW264.7 cells, such as inducible
NO synthase, cyclooxygenase-2, and interleukin-6 (IL-6). In the lipopolysaccharide-induced
sepsis mouse model, D25 significantly reduced p-eIF4E in spleen tissue
and decreased the expression of tumor necrosis factor α, interleukin-1β,
and IL-6, and it also reduced the production of reactive oxygen species,
resulting in improved organ injury caused by inflammation. This suggests
that D25 may provide a potential treatment for sepsis and sepsis-associated
acute spleen injury.