Design,synthesis and biological evaluation of novel compounds of BTK PROTAC
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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