Development of Nur77/TR3 Peptide Mimetics for the Treatment of Cancer

描述（申请人提供）：细胞凋亡被认为是控制癌症发生和进展的重要生物学过程，化疗药物的疗效很大程度上取决于其诱导细胞凋亡的能力。现代生物学表明，基于肿瘤细胞与正常细胞之间的分子差异来发现抗癌药物是一条可行的途径。Bcl-2是一种关键的抗凋亡蛋白，在大多数恶性肿瘤中过度表达，并有助于癌症的发展和耐药性。因此，靶向Bcl-2的药物具有治疗优势。最近，我们在癌细胞中发现了一种新的Nur77-Bcl-2凋亡通路，其中孤儿核受体Nur77（也称为TR3）从细胞核迁移到线粒体，并与Bcl-2相互作用诱导细胞色素c释放，从而引发细胞凋亡。重要的是，Nur77与Bcl-2的相互作用将Bcl-2从保护者转化为杀手，为开发更有效的抗癌药物提供了机会。我们假设从Nur77蛋白的bcl -2结合区衍生的肽可以开发为靶向表达bcl -2的癌细胞的治疗剂。在我们的初步研究中，我们发现含有Nur77蛋白9个氨基酸残基的细胞渗透性肽在体外和动物实验中有效地诱导癌细胞凋亡。与Nur77一样，该肽通过与Bcl-2的相互作用靶向线粒体并诱导Bcl-2构象改变。在STTR I期申请中，我们建议通过修饰Nur77先导肽来改善其药理和生物制药性能。我们的目标将通过三个目标来实现：(1)。利用氨基酸取代和肿瘤选择性归巢肽偶联设计合成Nur77肽（2）. 评估Nur77肽的线粒体靶向性、Bcl-2相互作用、构象改变和细胞凋亡诱导；(3)。评价Nur77肽的药代动力学、小鼠耐受性和体内疗效。我们的目标是确定一种稳定的，肿瘤选择性的，细胞渗透性的肽，具有最小的毒性和合适的药代动力学，用于II期开发和商业化。

DESCRIPTION (provided by applicant): Apoptosis is well recognized as an important biological process that controls cancer development and progression and the efficacy of chemotherapeutic drugs depends largely on their ability to induce apoptosis. Modern biology has suggested that cancer drug discovery based on molecular differences between tumor and normal cells is a feasible approach. Bcl-2, a critical anti-apoptotic protein, is overexpressed in the majority of malignancies and contributes to cancer development and drug resistance. Agents that target Bcl-2, therefore, offer a therapeutic advantage. Recently, we discovered a novel Nur77-Bcl-2 apoptotic pathway in cancer cells, in which orphan nuclear receptor Nur77 (also known as TR3) migrates from the nucleus to mitochondria where it interacts with Bcl-2 to induce cytochrome c release, which triggers apoptosis. Importantly, the interaction of Nur77 with Bcl-2 converts Bcl-2 from protector to killer, offering an opportunity to develop more effective anti-cancer agents. We hypothesize that peptides derived from the Bcl-2-binding region in Nur77 protein can be developed as therapeutic agents targeting Bcl-2-expressing cancer cells. In our preliminary studies, we found that a cell-permeable peptide with 9 amino acid residues from the Nur77 protein effectively induces apoptosis of cancer cells in vitro and in animals. The peptide, like Nur77, targets mitochondria through its interaction with Bcl-2 and induces Bcl-2 conformational change. In this STTR Phase I application, we propose to improve the pharmacological and biopharmaceutical properties by modifying the lead Nur77 peptide. Our goal will be accomplished by 3 aims: (1). Design and synthesis of Nur77 peptides using amino acid substitution and conjugation with a tumor selective homing peptide; (2). Evaluate Nur77 peptides for their mitochondrial targeting, Bcl-2 interaction, conformational change, and apoptosis induction; (3). Evaluate Nur77 peptides for their pharmacokinetics, tolerability in mice and in vivo efficacy. Our goal is to identify a stable, tumor-selective, cell-permeable peptide with minimal toxicity and suitable pharmacokinetics for Phase II development and commercialization.