Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth.
Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth.
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DOI：
10.1021/acs.jmedchem.1c01084
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发表时间：
2021-09
影响因子：
7.3
通讯作者：
Yun Han;Huimin Zhang;Shuxiang Wang;Bo Li;Kun Xing;Yuntao Shi;Hongxue Cao;Jian Zhang;Tong Tong-Tong;Jie Zang;Lihong Guan;Xiaoxiao Gao;Yuetong Wang;Dan Liu;Min Huang;Yongkui Jing;Linxiang Zhao
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作者：
Yun Han;Huimin Zhang;Shuxiang Wang;Bo Li;Kun Xing;Yuntao Shi;Hongxue Cao;Jian Zhang;Tong Tong-Tong;Jie Zang;Lihong Guan;Xiaoxiao Gao;Yuetong Wang;Dan Liu;Min Huang;Yongkui Jing;Linxiang Zhao
有丝分裂原活化蛋白激酶相互作用激酶（MNK）和前病毒整合在Maloney小鼠白血病病毒激酶（PIM）中是与酪氨酸激酶抑制剂耐药相关的细胞增殖信号通路的下游酶。MNK和PIM在调节癌蛋白的帽依赖性翻译方面具有互补作用。MNK和PIM的双重抑制剂尚未开发。我们开发了一种新的4，6-二取代吡啶并[3，2-d]嘧啶化合物21 o，其具有选择性抑制MNK和PIM的作用。21 o抑制MNK 1和MNK 2的IC 50分别为1和7 nM，抑制PIM 1、PIM 2和PIM 3的IC 50分别为43、232和774 nM。21 o抑制髓系白血病K562和MOLM-13细胞的生长，GI_（50）分别为2.1和1.2 μM。21 o降低了MNK和PIM的下游产物p-eIF 4 E和p-4 EBP 1以及帽依赖性蛋白c-myc、细胞周期蛋白D1和Mcl-1的水平。21 o抑制MOLM-13细胞异种移植物的生长而不引起明显的毒性。21 o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。
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.