Discovery and development of substituted tyrosine derivatives as Bcl-2/Mcl-1 inhibitors
Discovery and development of substituted tyrosine derivatives as Bcl-2/Mcl-1 inhibitors
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作为 Bcl-2/Mcl-1 抑制剂的取代酪氨酸衍生物的发现和开发
DOI：
10.1016/j.bmc.2018.08.030
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发表时间：
2018
影响因子：
3.5
通讯作者：
Fang Hao
中科院分区：
文献类型：
--
作者：
Liu Renshuai;Liu Lulu;Liu Tingting;Yang Xinying;Wan Yichao;Fang Hao
抗凋亡Bcl-2家族蛋白对癌细胞逃避凋亡至关重要，这使得它们成为癌症治疗的有吸引力的靶点。最近，发现一种先导化合物1适度抑制BH 3肽与Bcl-2蛋白的结合，Ki值为5.2 µM。在此基础上，开发了一系列取代的酪氨酸衍生物，并测试了它们与Bcl-2蛋白的结合亲和力。结果表明，这些化合物对Bcl-2和Mcl-1蛋白有较强的结合活性，但对Bcl-XL蛋白无明显的结合活性。化合物6 i对BH 3肽与Bcl-2和Mcl-1蛋白的结合有较好的抑制作用，其aKi值分别为450和190 nM，并显示出明显的抗肿瘤细胞增殖活性。
Anti-apoptotic Bcl-2 family proteins are vital for cancer cells to escape apoptosis, which make them attractive targets for cancer therapy. Recently, a lead compound1was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with aKivalue of 5.2 µM. Based on this, a series of substituted tyrosine derivatives were developed and tested for their binding affinities to Bcl-2 protein. Results indicated that these compounds exhibited potent binding affinities to Bcl-2 and Mcl-1 protein but not to Bcl-XLprotein. Promisingly, compound6iinhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with aKivalue of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.