标题：Discovery and development of substituted tyrosine derivatives as Bcl-2/Mcl-1 inhibitors
作者：Liu, Renshuai; Liu, Lulu; Liu, Tingting; Yang, Xinying; Wan, Yichao; Fang, Hao
作者机构：[Liu, Renshuai; Liu, Lulu; Liu, Tingting; Yang, Xinying; Fang, Hao] Shandong Univ, Sch Pharm, Key Lab Chem Biol, Dept Med Chem,Minist Educ, Jinan 2500 更多
通讯作者地址：[Fang, H]Shandong Univ, Sch Pharm, Dept Med Chem, 44 West Wenhua Rd, Jinan, Shandong, Peoples R China.
来源：BIOORGANIC & MEDICINAL CHEMISTRY
关键词：Apoptosis; Bcl-2; Mcl-1; Tyrosine; Anti-tumor
摘要：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 compound 1 was found to modestly inhibit the binding of BH3 peptide to Bcl-2 protein with a K, value of 5.2 mu M. 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-X-L protein. Promisingly, compound 6i inhibited the binding of BH3 peptide to Bcl-2 and Mcl-1 protein with a K-i value of 450 and 190 nM respectively, and showed obvious anti-proliferative activities against tested cancer cells.