TARGETING HER-2 PROTEIN FOR BREAST CANCER USING COMPUTATIONAL APPROACH

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 HER2蛋白的过度表达或激活常见于乳腺癌、卵巢癌和肺癌。用抗体阻断HER2介导的信号已被证明在抑制细胞生长方面是有效的。我们的假设是，基于HER2-Herceptin复合体结构设计的肽类药物将抑制HER2介导的细胞生长信号。通过分析HER2及其抗体(Herceptin)复合体的晶体结构，我们设计了几种肽模拟物来抑制HER2介导的细胞生长信号。其中两个化合物HERP5和HERP7对乳腺癌细胞具有抗增殖活性，IC50值分别为0.390 mM和0.143 mM。为了提高HERP5和HERP7的效力，我们对这些分子进行了结构修饰。采用计算对接方法研究HERP5和HERP7的不同类似物与HER2蛋白胞外区的相互作用。共有51个化合物与HER2蛋白对接，并分析了它们的结合模式。选择对接能较低的化合物进行化学合成，并对其生物活性进行了评价。用过表达HER2蛋白的BT474和SKBR3细胞株和不过表达HER2蛋白的MCF-7乳腺癌细胞株进行细胞培养试验，评估这些化合物的抗癌作用。结果表明，R3位含苯基的肽类化合物具有潜在的抗增殖活性。这些结果将有助于扩大我们对新型抗癌药物构效关系的研究，并有助于了解HER2蛋白对靶向乳腺癌的信号调制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overexpression or activation of HER2 protein occurs frequently in breast, ovarian, and lung cancers. Blocking of HER2-mediated signaling with antibodies has shown to be effective in inhibiting cell growth. Our hypothesis is that peptidomimetics designed based on the structure of HER2-herceptin complex will inhibit the HER2-mediated signal for cell growth. By analyzing the crystal structure of the HER2 and its antibody (herceptin) complex, we have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. Two of the compounds, HERP5 and HERP7, exhibited antiproliferative activity with IC50 values of 0.390 mM and 0.143 mM respectively, against breast cancer cell lines. To increase the potency of HERP5 and HERP7, we have modified these molecules structurally. Computational docking methods were used to explore the interactions of various analogs of HERP5 and HERP7 with the HER2 protein extracellular domain. A total of 51 compounds were docked to the HER2 protein, and their binding modes were analyzed. Compounds that exhibited low docking energy were chosen for chemical synthesis and their biological activity was assessed. The anticancer effect of these compounds was evaluated in cell culture assays using BT474 and SKBR3 cell lines that overexpress HER2 protein and MCF-7 breast cancer cell lines that do not overexpress HER2 protein. The results indicated that peptidomimetics with a phenyl group in the R3 position exhibit potential antiproliferative activity. These results will be useful to extend our studies on the structure-activity correlation of novel anticancer agents and to understand the modulation of signals mediated by HER2 protein to target breast cancer.