Objective To design and synthesize BTK PROTACs with ibrutinib analogues as ligands of BTK and thalidomide analogues as ligands of E3 ligase,and evaluate its in vitro activity.Methods As a starting material,3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine was used to modify and synthesize new BTK PROTACs by substitution,reduction amination,deprotection,hydrolysis and other reactions;the OCI-LY10 proliferative inhibitory activity and BTK degradation activity of the target compounds were determined by MTS and Western-blot;the binding mode of molecular ligands to BTK was determined by molecular docking.Results A total of 14 PROTACs were synthesized,and most of the compounds exhibited certain amount of in vitro activity,among which compound 15a showed excellent cell proliferative inhibitory activity(IC50=7.15 nmol·L-1)and BTK degradation activity(DC50<10 nmol·L-1).Conclusions BTK PROTACs with novel structure and excellent activity were synthesized,and the structure-activity relationship was preliminarily explored,which could provide a reference for further research on BTK PROTAC degrader.
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