SOS1/EPS8/ABI1靶向短肽抑制剂的设计合成及其抗卵巢癌转移活性的研究

卵巢癌的高转移倾向是其治疗失败的主要原因之一，研发以阻断癌细胞浸润转移为靶向的新型抗癌药物，对提高卵巢癌疗效具有重要意义。近年来，有学者成功利用短肽抑制剂阻断了蛋白间相互作用，进而阻断相关生物学效应，为肽类药物的研发提供了新的思路。我们的前期研究结果显示三重复合物SOS1/EPS8/ABI1是溶血磷脂酸诱导卵巢癌细胞转移信号通路的关键调节因子，其完整性可决定卵巢癌细胞的转移能力，提示SOS1/EPS8/ABI1可能成为有效的抗肿瘤治疗靶点。由于SOS1、EPS8、ABI1对Rac的活化缺一不可，且 既往文献报道ABI1可能作为支架蛋白连接SOS1及EPS8，故我们推测针对ABI1上介导其与SOS1及EPS8反应的位点，设计合成特异性短肽抑制剂，以阻断蛋白间的结合，破坏复合物的形成、抑制其功能，可望有效阻断卵巢癌细胞的迁移，从而为抗癌药物的研发提供初步的理论基础。

The high metastatic tendency of ovarian cancer is one of the main reasons for the failure of treatment. Developing novel anticancer drugs which target the invasion and metastasis process may be helpful in improving the curative effects of ovarian cancer. Recently, short peptide inhibitor has been reported could successfully block the protein-protein interaction, and in turn block the relevant biological events, which provides a clue for peptide-type drug researching. Our previous study demonstrates that SOS1/EPS8/ABI tri-complex is the key regulative factor in the signaling pathway for LPA induced ovarian cancer cell migration, and the integrity of SOS1/EPS8/ABI determines ovarian cancer metastasis. It indicates that SOS1/EPS8/ABI1 might be the target of the anticancer therapeutic approach. Since the requirement of all three members of SOS1/EPS8/ABI1 for Rac activation, and previous reports indicating ABI1 as a scaffold protein to hold together SOS1 and EPS8, we hypothesize that designed peptide inhibitor which targets the domain on ABI1 for EPS8 or SOS1 binding, could disrupt the protein-protein interaction, block the of tri-complex formation, and eventually inhibit the ovarian cancer cell migration. Our study will provide some theoretical basis for anti-cancer drug development.