抗凋亡Bcl-2蛋白（如Bcl-2、Bcl-xL、Mcl-1等）的过度表达，与肿瘤细胞逃避细胞凋亡密切相关，一直备受人们的关注。迄今唯一上市的Bcl-2选择性抑制剂ABT-199，因其与Mcl-1亲和力有限，对于Mcl-1过度表达的相关肿瘤效果不理想，往往需要与Mcl-1抑制剂进行联合用药。因此，发展Bcl-2/Mcl-1双靶点抑制剂为解决上述问题提供了新思路。申请人前期曾报道新型Bcl-2/Mcl-1双靶点抑制剂BPS34，该化合物不仅结构新颖，而且对Bcl-xL抑制活性较差，具有防止Bcl-xL受到抑制而引发血小板减少的潜能。本课题拟基于BPS34与靶点蛋白的结合模式，保留有效的活性片段，对其侧链或者母核进行结构改造，并通过多层级虚拟筛选、定向合成及体内外生物活性评价，以期发现新型高效的含氮杂环类Bcl-2/Mcl-1双靶点抑制剂，为抗肿瘤药物研究提供重要的实验基础和理论依据。

The overexpression of anti-apoptotic Bcl-2 proteins (such as Bcl-2, Bcl-xL, Mcl-1) is associated with the evasion of apoptosis for tumor cells, which is always concerned by people. So far, the only marketed Bcl-2 selective inhibitor ABT-199 has poor inhibitory activity against Mcl-1 and poor effect on tumor cells with high expression of Mcl-1 protein, so it needs to be combined with Mcl-1 inhibitors. Therefore, the development of Bcl-2/Mcl-1 dual-target inhibitor provides a new way to solve the above problems. In the previous study, we reported a novel Bcl-2/Mcl-1 dual-target inhibitor BPS34, which was not only novel in structure, but also had the potential to avoid thrombocytopenia caused by inhibition of Bcl-xL. In the on-going study, we will modify the side chains or the scaffold by keeping active fragments based on the interaction mode between the lead and target proteins. Through performing multi-level virtual screening, oriented synthesis, and biological activity evaluation in vitro and in vivo, we hope to find new nitrogen-containing heterocyclic derivatives as Bcl-2/Mcl-1 dual-target inhibitors with high efficiency and provide important experimental and theoretical basis for the research of antitumor drugs.