Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer.
Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer.
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DOI：
10.1111/cbdd.12453
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发表时间：
2015-06
影响因子：
3
通讯作者：
Jois S
中科院分区：
文献类型：
--
作者：
Kanthala S;Banappagari S;Gokhale A;Liu YY;Xin G;Zhao Y;Jois S
目前治疗HER 2过表达乳腺癌的方法是使用单克隆抗体或抗体与传统化疗剂或激酶抑制剂的组合。我们的方法是用肽模拟物靶向临床验证的HER 2结构域IV并抑制HER的蛋白质-蛋白质相互作用（PPI）。与抗体不同，肽模拟物在稳定性、修饰和分子大小方面具有优势。我们设计了肽模拟物（化合物5和9），它们与HER 2结构域IV结合，抑制蛋白质-蛋白质相互作用，并降低HER 2过表达的乳腺癌细胞的细胞活力。使用酶片段互补和邻近连接测定，我们已经表明肽模拟物抑制HER 2：HER 3的PPI。化合物5和9抑制异种移植小鼠模型中的肿瘤生长。此外，我们已经表明，与来自体内研究的组织样品中的对照相比，这些化合物抑制HER 2：HER 3的PPI和HER 2的磷酸化。还在小鼠血清中研究了化合物的稳定性，化合物表现出稳定性，半衰期长达3小时。这些结果表明，我们开发的新型肽模拟物靶向HER 2蛋白的胞外结构域并抑制HER 2：HER 3相互作用，提供了治疗HER 2阳性癌症的新方法。
The current approach to treating HER2-overexpressed breast cancer is the use of monoclonal antibodies or a combination of antibodies with traditional chemotherapeutic agents or kinase inhibitors. Our approach is to target clinically validated HER2 domain IV with peptidomimetics and inhibit the protein-protein interactions (PPI) of HERs. Unlike antibodies, peptidomimetics have advantages in terms of stability, modification, and molecular size. We have designed peptidomimetics (compounds 5 and 9) that bind to HER2 domain IV, inhibit protein-protein interactions, and decrease cell viability in breast cancer cells with HER2 overexpression. We have shown, using enzyme fragment complementation and proximity ligation assays, that peptidomimetics inhibit the PPI of HER2:HER3. Compounds 5 and 9 suppressed the tumor growth in a xenograft mouse model. Furthermore, we have shown that these compounds inhibit PPI of HER2:HER3 and phosphorylation of HER2 as compared to control in tissue samples derived from in vivo studies. The stability of the compounds was also investigated in mouse serum, and the compounds exhibited stability with a half-life of up to 3 h. These results suggest that the novel peptidomimetics we have developed target the extracellular domain of HER2 protein and inhibit HER2:HER3 interaction, providing a novel method to treat HER2-positive cancer.
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影响因子：
4.4
作者：
Banappagari S;Ronald S;Satyanarayanajois SD
通讯作者：
Satyanarayanajois SD
影响因子：
11.5
作者：
Esserman, Laura J.;DeMichele, Angela
通讯作者：
DeMichele, Angela
影响因子：
5.3
作者：
Lu, Chafen;Mi, Li-Zhi;Springer, Timothy A.
通讯作者：
Springer, Timothy A.
DOI：
10.1073/pnas.1633546100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Kumagai, T;Katsumata, M;Greene, MI
通讯作者：
Greene, MI
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U