新型BCL-2抑制剂的设计、合成及活性评价

Design,Synthesis and Activity Evaluation of Novel BCL-2 Inhibitors

通过研究BGB-11417与靶蛋白结合的相互作用,创造性的在P2口袋引入并环,合成了6个结构新颖的BCL-2抑制剂,产物经1H NMR和MS确证。以时间分辨荧光共振能量转移法(TR-FRET)测定目标化合物对BCL-2蛋白及BCL-2突变蛋白G101V和D103Y的体外抑制活性。活性结果表明化合物A、化合物B和化合物D对BCL-2及其突变蛋白G101V和D103Y有较好的抑制活性,可为合成活性更高的BCL-2抑制剂提供参考。

To synthesize a series of novel BCL-2 inhibitors and to determine their anticancer activity.By studying the interaction between BGB-11417 and BCL-2 protein,we creatively introduce bicyclic structure into P2 pocket.Six novel BCL-2 inhibitors were synthesized and their structures were confirmed by ^(1)H NMR spectra and MS.The inhibitory activity of the target compounds on BCL-2 and its mutant proteins GI01V and DI03Y in vitro was determined by time-resolved fluorescence resonance energy transfer method(TR-FRET).The results of biological evaluation indicated that compound A,compound B and compound D showed potent anticancer activities,which could provide a reference for synthesizing BCL-2 inhibitors with higher activity.