Synthesis Of Protein Kinase Inhibitor And Its Anti-cancer Activity

The more than500human protein kinases constitute a large family of enzymescatalyzing phosphorylation of Ser, Thr or Tyr residues in substrate proteins, andthese kinases are responsible for the control of a wide variety of signal transductionprocesses within the cell. Deregulated protein kinase activity has been implicated ina panel of diseases, including cancer, disorders of the immune system,neurodegenerative disorders, and etc. Selective protein kinase inhibitors are thereforeof great potentials in new drug development.Given that many natural indolocarbazole compounds, including staurosporine,K252a, Granulatimide, and etc, are ATP-competitive kinse inhibitor, it is of nosurprise that these natural indolocabazoles are typically non-selective kintaseinhibitors. Herein, we present the recent progress on our kinase inhibitor projectwhich created a new molecular scaffold to mimic the natural indolocarbazoles viathe application of click chemistry.Totally23new compounds were prepared at the initial proof-of-concept stage.Among them, one hit compound was discovered which showed potent growthinhibition of activity against tumor cell lines at1mΜ concentration level. In aone-dose-124-kinases-screening assay, this compound surprisingly showed greatselectivity. Only4members of these124kinases were remarkably prohibited by thiscompound at500nM. The IC50values of these4kinases were determined. And theATP-competition experiment confirmed this compound as an ATP competitiveinhibitor. Docking studies of some of these compounds to GSK-3β crystal structurewere performed, and consistent computational results to the assay date wereobtained.The triazole fragment was also replaced by pyrazole and iminazole fragment,3new compounds contained pyrazole fragment and3new compounds containediminazole fragment were prepared. The results of the MTT showed that the pyrazolecompounds were less active than the triazole compounds, while the inhibition activity of iminazole compounds against tumor cell was one magnitude more potentthan the hit compound.In order to study the substrate adaptability of the StaN which was responsiblefor the building of the second glycosidic linkage in the biosynthesis of staurosporine,we also prepared one substrate of the StaN through14steps.