Design,synthesis and biological activity evaluation of novel BTK PROTAC degrader
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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