Discovery ofa Novel MNK Inhibitor (NSP-1047)with In Vivo Anti-acute Myeloid LeukemiaActivity

Abstract 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.