School of Pharmacy, Chengdu Medical College, Chengdu 610500, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Bioorg Med Chem. 2019 Jun 1;27(11):2268-2279. doi: 10.1016/j.bmc.2019.04.022. Epub 2019 Apr 17.
MAP Kinase Interacting Serine/Threonine Kinase 1 (MNK1) play important roles in the signaling transduction of MAPK pathways. It is significantly overexpressed in renal clear cell carcinoma and head-neck squamous cell carcinoma tissues in both mRNA and protein levels. Based on the crystallographic structure of MNK1 protein and binding modes analysis of known MNK inhibitors, we have designed and synthesized a series of 4-aniline-thieno[2,3-d]pyrimidine derivatives as potential MNK1 inhibitors. These synthetic compounds are tested in biochemical and cell proliferation assays, and six of them display potent inhibitory capacity against MNK1 kinase and cancer cell lines. Compound 12dj with strongest inhibitory capacity is transferred to molecular mechanism studies, and the results indicated that 12dj remarkably suppresses the phosphorylation of EIF4E, a substrate of MNK1. And the expression levels of MNK1, ERK1/2 and pERK1/2 are not affected by compound 12dj incubation in SUNE-1 and 786-O cells. In summary, our works suggested that these novel 4-aniline-thieno[2,3-d]pyrimidine based MNK1 inhibitors might be attractive lead compounds for targeted therapy of renal cell carcinoma and nasopharyngeal carcinoma.
丝裂原活化蛋白激酶相互作用丝氨酸/苏氨酸激酶 1（MNK1）在 MAPK 信号通路的信号转导中发挥重要作用。它在肾透明细胞癌和头颈部鳞状细胞癌组织中的 mRNA 和蛋白水平均显著过表达。基于 MNK1 蛋白的晶体结构和已知 MNK 抑制剂的结合模式分析，我们设计并合成了一系列 4-苯胺-噻吩并[2,3-d]嘧啶衍生物作为潜在的 MNK1 抑制剂。这些合成化合物在生化和细胞增殖测定中进行了测试，其中有 6 种化合物对 MNK1 激酶和癌细胞系表现出很强的抑制能力。具有最强抑制能力的化合物 12dj 被转移到分子机制研究中，结果表明 12dj 显著抑制 MNK1 的底物 EIF4E 的磷酸化。并且化合物 12dj 孵育不会影响 SUNE-1 和 786-O 细胞中 MNK1、ERK1/2 和 pERK1/2 的表达水平。总之，我们的工作表明，这些新型基于 4-苯胺-噻吩并[2,3-d]嘧啶的 MNK1 抑制剂可能是肾细胞癌和鼻咽癌靶向治疗的有吸引力的先导化合物。
