Design,synthesis and preliminary activity evaluation of novel Bcl-2 protein inhibitors
Objective To design and synthesize a series of novel small molecule inhibitors of Bcl-2 and test their effects on Bcl-2,Bcl-2 G101V(Bcl-2 mutant)and BH3-only protein interactions,and initially investigate their constitutive relationship,which will provide reference for subsequent related studies.Methods The clinical compound BGB-11417 was used as the lead compound,a novel small molecule inhibitor of Bcl-2 containing a spirocyclic structure was designed by scaffold hopping and other methods.The target compounds were synthesized from benzaldehyde by substitution,cyclization and coupling reactions,and the structures were determined by 1 H-NMR and LC-MS.Time-resolved fluorescence resonance energy transfer(TR-FRET)was used to evaluate the inhibitory ability of the target compounds on the interactions of Bcl-2,Bcl-2 G101V(Bcl-2 mutant)with BH3-only protein.Results A total of eight novel spiro Bcl-2 small molecule inhibitors were synthesized,among which 29a[IC50(Bcl-2):0.8 nmol·L-1,IC50(Bcl-2 G101V):55.41 nmol·L-1]and 29d[IC50(Bcl-2):0.27 nmol·L-1,IC50(Bcl-2 G101V):18.65 nmol·L-1]showed good inhibitory activities on the interaction of Bcl-2 and Bcl-2 G101V with BH3-only protein.Conclusion A novel method for the synthesis of spiro Bcl-2 small molecule inhibitors has been established,and new compounds with good inhibitory activity against the interaction of Bcl-2 and Bcl-2 G101V(Bcl-2 mutant)with BH3-only proteins have been found,among which 29d is valuable for further study.
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