Mitogen-activated
protein kinase-interacting kinases (MNKs) and
provirus integration in maloney murine leukemia virus kinases (PIMs)
are downstream enzymes of cell proliferation signaling pathways associated
with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have
complementary effects to regulate cap-dependent translation of oncoproteins.
Dual inhibitors of MNKs and PIMs have not been developed. We developed
a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine
compound 21o with selective inhibition of MNKs and PIMs.
The IC50’s of 21o to inhibit MNK1 and
MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are
43, 232, and 774 nM, respectively. 21o inhibits the growth
of myeloid leukemia K562 and MOLM-13 cells with GI50’s
of 2.1 and 1.2 μM, respectively. 21o decreases
the levels of p-eIF4E and p-4EBP1,
the downstream products of MNKs and PIMs, as well as cap-dependent
proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the
growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a
good pharmacokinetic profile.
Fibroblast growth factor 21 (FGF-21) is a major paracrine and endocrine regulator of metabolic homeostasis. Here we demonstrate that FGF-21 is also a potent mediator of innate immunity. Double-staining flow cytometry identified neutrophils and monocytes as the main sources of FGF-21 among circulating leukocytes. Functional assays showed that FGF-21 stimulates phagocytosis and production of reactive oxygen species in neutrophil-like HL-60 cells and monocytic THP-1 cells. The mechanism of action of FGF-21 was observed to involve FGF receptor activation, signal transduction through the PI3K/Akt pathway, and stimulation of NADPH oxidase activity. This study indicates that FGF-21 could be an attractive target for the management of inflammatory disorders.
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