Position of lipidation influences anticancer activity of Smac analogs.
Position of lipidation influences anticancer activity of Smac analogs.
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脂化位置影响 Smac 类似物的抗癌活性。
DOI：
10.1016/j.bmcl.2019.04.041
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发表时间：
2019
影响因子：
2.7
通讯作者：
Ruchala,Piotr
中科院分区：
文献类型：
--
作者：
Micewicz,EwaD;Nguyen,Christine;Micewicz,Alina;Waring,AlanJ;McBride,WilliamH;Ruchala,Piotr
合成了一小群脂质偶联的Smac模拟物，以探讨脂化位置对整体抗癌活性的影响。具体来说，新化合物在3位和c端被脂质修饰。也合成了先前描述的2位脂化类似物M11。在50种不同的癌细胞系中，对在2、3和c端位置脂化的Smacs迷你文库进行了广泛的体外筛选，发现脂化位置和脂质类型都会影响它们的抗癌活性和癌症类型特异性。此外，当与menin-MLL1蛋白相互作用抑制剂联合使用时，位置2修饰的类似物SM2显示出强大的协同抗癌特性。最有希望的脂质偶联类似物SM2和SM6在临床前小鼠模型中皮下给药时显示出良好的药代动力学和体内活性。总之，我们的研究结果表明，Smacs的脂质修饰可能是开发抗癌治疗线索的可行方法。
A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensivelyin vitroagainst a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin–MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics andin vivoactivity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
2.7
作者：
Chua K;Fung E;Micewicz ED;Ganz T;Nemeth E;Ruchala P
通讯作者：
Ruchala P
DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
影响因子：
7.3
作者：
Sheng, Rong;Sun, Haiying;Liu, Liu;Lu, Jianfeng;McEachern, Donna;Wang, Guanfeng;Wen, Jianfeng;Min, Ping;Du, Zhenyun;Lu, Huirong;Kang, Sanmao;Guo, Ming;Yang, Dajun;Wang, Shaomeng
通讯作者：
Wang, Shaomeng
1,1,3,3-四甲基胍存在下半胱氨酸的高效 S-烷基化
影响因子：
1.8
作者：
M. Włostowski;Sylwia Czarnocka;P. Maciejewski
通讯作者：
P. Maciejewski