Optimization of 4‑Aniline Substituted Pyrido[3,2‑d]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 1 with a pyrido[3,2-d]pyrimidine core. We optimized the properties of 1 through bioisostere replacement and synthesized a new group of compounds. Among these compounds, 2j exhibited improved selectivity and kinase inhibition activities, with IC50 values of 32, 3, and 37 nM against Mnk1, Mnk2, and Pim1, respectively. 2j displayed better antiproliferative effects in leukemia cell lines with cell cycle arrest and apoptosis induction. Western blot analysis revealed that 2j decreased the levels of Mnk substrate p-eIF4E and Pim substrate p-4EBP1 in leukemia cell lines. 2j exhibited improved water solubility and pharmacokinetic profile with potent in vivo antileukemia effects in MOLM-13 xenografts. 2j emerges as a novel dual Pim/Mnk inhibitor with potential for further development as an antileukemic agent.