Design,Synthesis And Activity Studies Of NEK2 Inhibitors MBM-17 And MBM-55 Analogs

NEK2,as a threonine/serine kinase,plays an important role in regulating the mitotic process of cells,one of the characteristics of cancer cells is that the mitotic process is disordered.At the same time,the overexpression of NEK2 has a great effect on tumor cell proliferation,drug resistance,metastasis deterioration and mitotic instability.Therefore,NEK2 can be used as a target for cancer therapy.Although many studies have been done on NEK2 kinase and its corresponding inhibitors,so far only a few small molecular inhibitors have been reported,they have only kinase and cell activity,and cell activity is not very ideal.The study of antitumor activity in vivo has only been reported in our group.Among them,compounds MBM-17 and MBM-55 have good kinase and cell activity,but their pharmacokinetic and pharmacodynamic results are not very ideal.And a good combination of pharmacokinetic and pharmacodynamic NEK2 inhibitors,not to mention clinical lead compounds.Therefore,it is necessary to develop a class of inhibitors with high activity,high selectivity and good biological results for NEK2 kinase.Therefore,the concept,biological function and relationship with tumor of NEK2 are summarized in this paper.Secondly,we analyzed the two compounds,MBM-17 and MBM-55,which had excellent kinase activity and tumor cell activity,and concluded that the solubilizing group N,N-dimethylethanamine portion has an adverse effect on the pharmacokinetics and pharmacodynamics,and the cell activity is not excellent enough,so we have retained the imidazolido [1,2-a] pyridine skeleton,The strategy of drug design based on activity was used to modify and synthesize this group,which mainly changed to nitrogen-containing heterocyclic ring,and changed its connecting position from 7-bit to 8-bit.Then,we changed the benzene ring of aromatic group into thiophene ring by means of molecular blending strategy,in order to further improve the tumor cell inhibitory activity of these inhibitors.Finally,by consulting the relevant literature,we find that Idrees M.,in the design of a new type of HIV-1 Vif antagonist,the bielectronic isosteric strategy was used to replace the amide bond of the lead compound with dioxazole and triazole groups.The results showed that the antiviral activity of the compound was increased by 5 times after the substitution of amide bond with bielectronic isochron triazole.In addition,triazole is not easy to be metabolized in human body,which improves the metabolic stability of compounds.In the previous studies of NEK2 inhibitors,the dioxazole and triazole groups were not introduced into the structure of the compounds.Inspired by this,in order to improve the metabolic stability and structure diversity of compounds,we also tried to modify the structure of the compound MBM-55 and introduce the dioxazole and triazole groups.In the end,we synthesized 11 compounds of gastric cancer cell activity better than that of MBM-55,and the best activity of CYZ-2002 was 17 times higher than that of MBM-55,which reached 38 nM.in the end,the cell activity of 11 compounds was higher than that of MBM-55,and the cell activity of 11 compounds was higher than that of MBM-55.The present invention is a novel NEK2 inhibitor based on such detomidine and[1,2-a],which is a framework structure,and has the highest inhibitory activity on gastric cancer cells in the derivative of which the group modification is carried out,thus having a good tumor treatment prospect.