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-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC₅₀’s of 21o 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. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI₅₀’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels of p-eIF4E and p-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.

中文翻译：

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优化 4,6-二取代吡啶并[3,2-d]嘧啶作为双重 MNK/PIM 抑制剂抑制白血病细胞生长

丝裂原活化蛋白激酶相互作用激酶 (MNK) 和马洛尼鼠白血病病毒激酶 (PIM) 中的原病毒整合是细胞增殖信号通路的下游酶，与酪氨酸激酶抑制剂的耐药性相关。MNK 和 PIM 具有互补作用，可调节癌蛋白的帽依赖性翻译。尚未开发出 MNK 和 PIM 的双重抑制剂。我们开发了一种新型的 4,6-二取代吡啶并[3,2- d ]嘧啶化合物21o，具有选择性抑制 MNK 和 PIM。的IC ₅₀的的21°以抑制MNK1和MNK2是1和7 nM的和那些以抑制PIM1，PIM2，PIM3和分别为43，232，和774纳米。21度抑制髓性白血病 K562 和 MOLM-13 细胞的生长，GI ₅₀分别为 2.1 和 1.2 μM。21o降低p -eIF4E 和p -4EBP1、MNK 和 PIM 的下游产物以及帽依赖性蛋白 c-myc、细胞周期蛋白 D1 和 Mcl-1 的水平。21o抑制 MOLM-13 细胞异种移植物的生长而不会引起明显的毒性。21o是一种创新的 MNK/PIM 双重抑制剂，具有良好的药代动力学特征。