PIM-1/MNKs激酶双重抑制剂的设计合成与抗肿瘤活性研究

以前期研究得到的具有PIM-1和MNK2双重抑制活性的PTZ510和PPM103为先导化合物，基于PIM-1与MNK激酶活性口袋的结构特征，设计合成4,6-双取代吡啶并三嗪类化合物和4,6-双取代吡啶并嘧啶类化合物；进行PIM-1/MNKs激酶活性筛选，选取PIM-1/MNKs高表达的肿瘤细胞株考察抑制剂的生长抑制、周期阻滞及诱导凋亡作用；选择活性化合物，考察其对PIM-1/MNKs通路中p-BAD、p-eIF4E、p-4E-BP1等蛋白表达的影响，确定该类化合物的作用机制；探讨PIM-1/MNKs双靶点抑制剂的体内抗肿瘤效果，寻找活性强选择性好的PIM-1/MNKs激酶双重抑制剂。

A series of novel 4,6-bis-substituted pyridine-triazines and 4,6-bis-substituted pyridine-pyrimidines will be designed and synthesized by analyzing the characteristics of PIM-1 and MNKs kinases active pockets, which is based on compounds PTZ510 and PPM103 with moderate inhibitory activities against PIM-1 and MNK2. The inhibitory effects of the compounds towards PIM-1 and MNKs will be determined, the anti-proliferation, cell cycle arrest and apoptosis induction effects against target-high-expressing tumor cell lines will be investigated, and the effects upon PIM-1/MNKs signaling will be studied through evaluating the levels of p-BAD、p-eIF4E、p-4E-BP1. Dual PIM-1/MNKs inhibitors will be further studied with their in vivo antitumor activities. We aim to develop potent and selective dual PIM-1/MNKs inhibitors as novel antitumor agents.