Objective To design and synthesize novel Bruton's tyrosine kinase protac(BTK PROTAC)molecules,and evaluate their degradation activity towards BTK protein in vitro.Methods With clinical compound NX-5968 from Nurix Therapeutics as a lead compound,its interaction with the target protein was analyzed.A series of novel BTK PROTACs were successfully synthesized by structural modification by introducing a skeleton transition of cyclic substitution for pyrazine amine.The kinase activity,cell proliferation inhibitory activity,and BTK degradation activity of the target compounds were measured by time-resolved fluorescence resonance energy transfer(TR-FRET),MTS and Western blot,respectively.Results Totally 6 target compounds were synthesized(compound B～G).The activity test showed that most compounds had excellent cell proliferation inhibition and BTK degradation.Compound B presented better BTK degradation ability,with a DC50 of about 0.1 nmol·L-1.Conclusion Based on NX-5948,a class of novel BTK PROTACs are designed and synthesized by skeleton transition,and their structure-activity relationship is preliminarily explored,providing reference for in-depth research on BTK PROTAC degraders.
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