Discovery of a Novel MNK Inhibitor (NSP-1047) with In Vivo Anti-acute Myeloid Leukemia Activity

MAPK-interacting kinases (MNKs) phosphorylate the eukaryotic
initiation
factor 4E (eIF4E), critical for cap-dependent translation. The MNK/eIF4E
pathway plays a role in the development and progression of various
hematological and solid tumors. Here, we report the discovery of a
novel polycyclic compound 21e (NSP-1047), which inhibits
MNK1 and MNK2 with high potency, leading to a reduction in the phosphorylation
of eIF4E. NSP-1047 shows strong in vitro antiproliferative activity
against multiple acute myeloid leukemia (AML) cell lines. Meanwhile,
it enhances anticancer immune responses by downregulating the expression
of immune checkpoint proteins and suppressing the secretion of inflammatory
cytokines. NSP-1047 displays excellent ADME and pharmacokinetic properties,
and encouraging safety profiles, with a highest nonsevere toxic dose
(HNSTD) of 750 and 200 mg/kg for SD rats and Beagle dogs, respectively.
In vivo efficacy evaluation in AML xenografts demonstrates significant
tumor suppression, with tumor regression observed at tolerated doses,
both as monotherapy and in combination with Ara-C or venetoclax.