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Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-13 , DOI: 10.1021/acs.jmedchem.1c01084
Yu Han 1 , Huimin Zhang 2 , Shuxiang Wang 1 , Bo Li 1 , Kun Xing 1 , Yuntao Shi 1 , Hongxue Cao 1 , Jian Zhang 1 , Tong Tong 1 , Jie Zang 1 , Lihong Guan 1 , Xiaoxiao Gao 2 , Yuetong Wang 2 , Dan Liu 1 , Min Huang 1 , Yongkui Jing 2 , Linxiang Zhao 1
Affiliation  

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:


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



丝裂原激活蛋白激酶相互作用激酶 (MNK) 和马洛尼鼠白血病病毒激酶 (PIM) 中的前病毒整合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 在调节癌蛋白的帽子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出来。我们开发了一种新型 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 的作用。 21o抑制MNK1和MNK2的IC 50分别为1和7nM,抑制PIM1、PIM2和PIM3的IC 50 分别为43、232和774nM。 21o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。 21o降低p -eIF4E 和p -4EBP1(MNK 和 PIM 的下游产物)以及帽依赖蛋白 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引起明显的毒性。 21o代表了一种创新的双重 MNK/PIM 抑制剂,具有良好的药代动力学特征。
更新日期:2021-09-23
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