TARGETING HER-2 PROTEIN FOR BREAST CANCER USING COMPUTATIONAL APPROACH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 生长因子是细胞增殖的重要介质。生长因子与其受体的相互作用产生信号转导。这些受体蛋白的胞内结构域是蛋白酪氨酸激酶。这些受体的过度表达或活化导致不受控制的细胞增殖。表皮生长因子受体（EGFR）激酶和相关的人表皮生长因子受体-2（HER-2）在癌症中具有重要意义。HER-2的过度表达或激活经常发生在乳腺癌、卵巢癌和肺癌中。HER-2已成为乳腺癌治疗的重要靶点。基于HER-2：Herceptin复合物的晶体结构，我们设计了几种肽/肽模拟物来抑制HER-2与其他分子的相互作用。其中两种化合物（HERP 5和HERP 7）表现出抗增殖活性，对过表达HER-2蛋白的SKBR 3细胞系（乳腺癌细胞系）的IC 50值分别为0.390 μ M和0.143 μ M。所设计的化合物可以阻断HER-2与诱导信号通路的其他ErbB受体蛋白的相互作用。在本提案中包含的研究中，我们将研究HERP 5和HERP 7的化学多样性。我们将利用一个国家的最先进的计算对接，这代表在硅片筛选方法，以确定化合物可能具有所需的生物活性。HERP 5和HERP 7的类似物将对接到报告的HER-2蛋白质晶体结构。将通过实验评价分析得到的低能对接结构的抗癌活性。该项目用计算方法解决了生物学中信号转导的一个重要方面。与该项目有关的计算工作将利用LBRN设施进行。

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. Growth factors are important mediators of cell proliferation. The interaction of growth factors with their receptors generates signal transduction. The intracellular domains of these receptor proteins are protein tyrosine kinases. The overexpression or activation of these receptors results in uncontrolled cell proliferation. Epidermal growth factor receptor (EGFR) kinase and the related human epidermal growth factor receptor-2, (HER-2) have important implications in cancer. The overexpression or activation of HER-2 occurs frequently in breast, ovarian, and lung cancers. HER-2 has become an important therapeutic target in breast cancer. Based on the crystal structure of HER-2:herceptin complex, we have designed several peptides/peptidomimetics to inhibit HER-2 interaction with other molecules. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC50 values of 0.390 ¿M and 0.143 ¿M against SKBR3 cell lines (breast cancer cell lines), which overexpress HER-2 protein. The designed compounds may block HER-2 interaction with other ErbB receptor proteins that induce signaling pathways. In the studies included in the present proposal we will investigate the chemical diversity of HERP5 and HERP7. We will exploit a state-of the-art computational docking, which represents in-silico screening approach to identify compounds likely to have desired biological activity. Analogs of HERP5 and HERP7 will be docked to reported HER-2 protein crystal structure. The low-energy docked structures resulting from the analysis will be evaluated experimentally for their anticancer activity. The project addresses an important aspect of signal transduction in biology with computational method. Computational work related to this project will be carried out by using LBRN facilities.