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

描述(申请人提供)：细胞凋亡被公认为控制癌症发展和进展的一个重要的生物过程，化疗药物的疗效在很大程度上取决于它们诱导细胞凋亡的能力。现代生物学已经表明，基于肿瘤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是一种重要的抗细胞凋亡蛋白，在大多数恶性肿瘤中过表达，并与肿瘤的发生和耐药有关。因此，靶向Bcl-2的药物提供了治疗优势。最近，我们在癌细胞中发现了一种新的凋亡途径，即孤儿核受体Nur77(又称TR3)从细胞核迁移到线粒体，在线粒体上与Bcl-2相互作用，诱导细胞色素c释放，从而触发细胞凋亡。重要的是，Nur77与Bcl2的相互作用将Bcl2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。我们推测，来自Nur77蛋白中的Bcl2结合区的多肽可以被开发成针对表达Bcl2的癌细胞的治疗药物。在我们的初步研究中，我们发现了一种含有Nur77蛋白9个氨基酸残基的细胞通透性多肽，在体外和动物体内都能有效地诱导癌细胞凋亡。与Nur77一样，这种多肽通过与Bcl2的相互作用来靶向线粒体，并诱导Bcl2的构象变化。在这个STTRI阶段的应用中，我们建议通过修饰主肽Nur77来改善其药理和生物药学特性。我们的目标将通过三个目标来实现：(1)。用氨基酸取代和与肿瘤选择性归巢多肽偶联的方法设计合成Nur77多肽；评价Nur77多肽的线粒体靶向性、Bcl2相互作用、构象变化和诱导细胞凋亡；(3)评价Nur77肽在小鼠体内的药代动力学、耐受性和体内疗效。我们的目标是找到一种稳定的、肿瘤选择性的、细胞渗透性的、毒性最小的多肽，并为第二阶段的开发和商业化提供合适的药代动力学。

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.