Design,synthesis And Biological Activity Study Of Anticancer Drugs Based On Structure Of Nik And IDH1^R132H

NF-?B-inducing kinase?NIK?also known as MAPK kinase kinase14?MAP3K14?is a serine/threonine kinase and a member of MAP3K family.NIK is a critical kinase of NF-?B classical pathway.Overexpression of NIK led to acvation of NF-?B,contributed to the development various cancers such as multiple myeloma,hodgkin lymphoma,peripheral T cell lymphoma and other solid tumor.Isocitrate dehydrogenase-1 plays an important role in the tricarboxylic acid cycle,which can catalyze the oxidative decarboxylation of isocitrate to?-ketoglutarate.All of the mutant IDH1 can reduce?-KG to D-2-hydroxyglutaric acid?2-HG?to cause the development of some cancers.Studies have shown that many cancers such as glioma,acute myeloid leukemia related closed to IDH1 mutation,especially the R132H.As the result,development of potent and specific NIK inhibitors and IDH1^R132H inhibitors becomes useful for treating these diseases.Based on NIK,previously,according to twenty five NIK inhibitors,QSAR model established by MD-SVR was applied to design novel compound,Then three NIK aminopyrimidine indole alkynyl alcohols derivatives?NIK-1^NIK-3?with promising activities were selected and synthesized.Three compounds exhibited good NIK inhibitor activities.The experimental results have good correlation with their predictive value.In addition,three novel NIK azaindole aminopyrimidine alkynyl alcohols derivatives?NIK-4^NIK-6?were designed and synthesized according to the biological electronics row principle.The structures were confirmed by ¹H NMR etc.Besides,this paper established NIK inhibitor molecular docking model with promising predictive ability by using Discovery Studio 2.5/LigandFit module.Receiver operating characteristic curves?ROC?were applied as a method of validation to evaluate the accuracy of the established model.Jain was selected as the best score function.Through the screening based on Specs database,9 compounds were obtained,among them four compound has display certain inhibitory activity with inhibition ratio of 27.6%,26.2%,26.2%and 24.3%respectively at 20?g/mL..Based on IDH1^R132H,a ccording to marine alkaloids meridianin C from high-throughput screening,a IDH1^R132H inhibitors with medium inhibitory,22 amino pyrimidine derivatives?IDH1-1^IDH1-22?were designed and synthesized by classical drug design principles,such as structure-based and biological electronics row principle.The structure of compounds was confirmed by ¹H-NMR.The results showed that most compounds exhibited high potency against IDH1^R132H.Among them,the compound IDH1-12 exhibited potent inhibitory activity with IC₅₀=948nM.In addition,based on the structure of IDH1^R132H,this paper astablished IDH1^R132H inhibitor molecular docking model with strong predict ability by using Discovery Studio 2.5/LigandFit module.RMSD were applied to select-PMF as the best score function.Nine compounds were obtained through the Virtual Screening.Among them,one compound has potent inhibition with value of 46.5%at 10?g/mL.