Optimization of 4,6-Disubstituted Pyrido[3,2-]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth.

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-]pyrimidine compound with selective inhibition of MNKs and PIMs. The IC's of 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. inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI's of 2.1 and 1.2 μM, respectively. decreases the levels of -eIF4E and -4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.