Optimization of 4-Aniline Substituted Pyrido[3,2- <i>d</i> ]pyrimidine Derivatives as Pim/Mnk Dual Inhibitors with Antileukemia Activity

Provirus integration in Moloney murine leukemia virus (Pim) and mitogen-activated protein kinase-interacting kinase (Mnk) cooperatively activate the cap-dependent protein translation and are being used as targets to develop anticancer agents. We reported the first dual Pim/Mnk inhibitor <b>1</b> with a pyrido[3,2-<i>d</i>]pyrimidine core. We optimized the properties of <b>1</b> through bioisostere replacement and synthesized a new group of compounds. Among these compounds, <b>2j</b> exhibited improved selectivity and kinase inhibition activities, with IC₅₀ values of 32, 3, and 37 nM against Mnk1, Mnk2, and Pim1, respectively. <b>2j</b> displayed better antiproliferative effects in leukemia cell lines with cell cycle arrest and apoptosis induction. Western blot analysis revealed that <b>2j</b> decreased the levels of Mnk substrate p-eIF4E and Pim substrate p-4EBP1 in leukemia cell lines. <b>2j</b> exhibited improved water solubility and pharmacokinetic profile with potent <i>in vivo</i> antileukemia effects in MOLM-13 xenografts. <b>2j</b> emerges as a novel dual Pim/Mnk inhibitor with potential for further development as an antileukemic agent.