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。 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激活会导致细胞不受控制的增殖。表皮生长因子受体(EGFR)激酶及其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的过度表达或激活常见于乳腺癌、卵巢癌和肺癌。HER-2已成为乳腺癌治疗的重要靶点。根据HER-2：Herceptin复合体的晶体结构，我们设计了几种多肽/模拟多肽来抑制HER-2与其他分子的相互作用。其中两个化合物(HERP5和HERP7)具有抗增殖活性，对高表达HER-2蛋白的SKBR3细胞株的IC50值分别为0.390和0.143？M。设计的化合物可能会阻止HER-2与其他诱导信号通路的ErbB受体蛋白的相互作用。在本提案所包括的研究中，我们将调查HERP5和HERP7的化学多样性。我们将利用最先进的计算对接，这代表了电子筛选方法来识别可能具有预期生物活性的化合物。HERP5和HERP7的类似物将对接到已报道的HER-2蛋白晶体结构。分析得到的低能对接结构将通过实验对其抗癌活性进行评估。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使用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.