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

开发用于治疗癌症的 Nur77/TR3 肽模拟物

• 批准号: 7161517
• 负责人: Kanyin E Zhang
• 金额: $ 26.96万
• 依托单位: VIVO LABORATORY, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161517
• 关键词: apoptosis; neoplasm /cancer; peptides

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.

描述（由申请人提供）：细胞凋亡被公认为控制癌症发展和进展的重要生物学过程，化疗药物的疗效主要取决于其诱导细胞凋亡的能力。现代生物学已经表明，基于肿瘤细胞和正常细胞之间的分子差异来发现癌症药物是一种可行的方法。Bcl-2是一种重要的抗凋亡蛋白，在大多数恶性肿瘤中过表达，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Nur 77-Bcl-2凋亡途径，其中孤儿核受体Nur 77（也称为TR 3）从细胞核迁移到线粒体，在线粒体中与Bcl-2相互作用以诱导细胞色素c释放，从而引发凋亡。重要的是，Nur 77与Bcl-2的相互作用将Bcl-2从保护者转变为杀手，为开发更有效的抗癌药物提供了机会。我们假设Nur 77蛋白中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Nur 77蛋白中具有9个氨基酸残基的细胞渗透性肽在体外和动物中有效诱导癌细胞凋亡。该肽与Nur 77一样，通过与Bcl-2相互作用靶向线粒体并诱导Bcl-2构象变化。在该STTR I期申请中，我们提出通过修饰前导Nur 77肽来改善药理学和生物制药学性质。我们的目标将通过三个目标来实现：（1）。使用氨基酸取代和与肿瘤选择性归巢肽缀合的Nur 77肽的设计和合成;（2）.评估Nur 77肽的线粒体靶向、Bcl-2相互作用、构象变化和凋亡诱导;（3）.评估Nur 77肽的药代动力学、小鼠耐受性和体内功效。我们的目标是确定一种稳定的，肿瘤选择性的，细胞可渗透的肽，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。