The Development of Screening Assays For Novel Inhibitors Of ARNO And Its Effector

新型ARNO抑制剂及其效应物筛选方法的研究进展

• 批准号: 8680032
• 负责人: DEAN Yaw LI
• 金额: $ 29.56万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680032
• 关键词: ADP-ribosylation factor 6; Accounting; Address; Adhesions; Affect; American; American Cancer Society; Apoptosis; Biochemical; Biological; Biological Assay; Blood; Blood Vessels; Breast; Breast Carcinoma; Cancer Biology; Cause of Death; Cell Lineage; Cell Proliferation; Cell division; Cell physiology; Cell surface; Cellular Assay; Cessation of life; Collaborations; Colon; Data; Development; Diagnosis; Disease; Effectiveness; Endothelium; Epidermal Growth Factor Receptor; Evaluation; Family; Germany; Growth; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Heart Diseases; In Vitro; Institution; LOX gene; Laboratories; Libraries; Life; Ligands; Lung; MEKs; Malignant Neoplasms; Melanoma Cell; Molecular; Molecular Bank; Monomeric GTP-Binding Proteins; Mutation; NIH Program Announcements; Neoplasm Metastasis; Oncogenic; Pathologic Neovascularization; Pathway interactions; Play; Positioning Attribute; Prostate; Proteins; Ras/Raf; Receptor Activation; Receptor Protein-Tyrosine Kinases; Rectum; Research; Research Proposals; Resistance; Role; Signal Pathway; Skin; Therapeutic; Therapeutic Intervention; Thyroid Gland; Tumor Cell Line; United States; United States National Institutes of Health; Universities; Urinary tract; Utah; Vascular Endothelial Growth Factors; Xenograft Model; angiogenesis; anticancer activity; assay development; base; cadherin 5; cancer therapy; cell motility; combat; female reproductive system; high throughput screening; inhibitor/antagonist; melanoma; molecular imaging; neoplastic cell; novel; receptor; screening; small molecule; tool; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States-second only to diseases of the heart-and accounts for about 23% of all deaths. Although significant progress has been made in the treatment of many cancers, it is estimated that in 2010, 569,490 Americans will die from these diseases (Cancer Facts and Figures 2010, American Cancer Society) and there is as yet no efficacious treatment for many forms of cancers. The molecular complexity of cancer makes the identification of additional oncogenic pathways amenable to therapeutic intervention paramount. In June 2010, NIH posted a program announcement (PA-10- 213) for the Development of Assay for High-throughput Screening for Use in Probe and Pre-therapeutic Discovery to encourage the development of novel, scientifically outstanding assays that have the potential to be developed into high-throughput screens (HTS) of relevant, high priority disease targets both for the identification of small molecule tools and therapeutic candidates. Together, we and our collaborators present data that provide compelling evidence that the inhibition of cytohesins, the guanine nucleotide exchange factors that activate Arf family GTPases, produces anticancer activity in vastly different cell lineages. Further, we demonstrate that this inhibition reduces in vitro proliferation and invasion in the context of Ras/Raf/ERK constitutive activation. Mutations of these downstream components of receptor tyrosine kinase signaling pathways have greatly limited the utility and effectiveness of currently available cancer therapies. Therefore, we believe targeting the cytohesin, ARNO, and its effector, Arf6, may produce promising new small molecule inhibitors useful at combating both innate and acquired chemotherapeutic resistance. In this application we seek to specifically address the need defined by NIH and present a strategy to developing assays amenable to a HTS campaign intended for the identification and evaluation of ARNO and/or Arf6 negative modulators. If successful, we will then seek to automate these screens through collaborations with the NIH's recently launched Molecular Libraries and Imaging initiative or other institutions with access to large, diverse compound libraries. In the long term, this strategy promises to identify new small molecule probe and pre-therapeutic compounds against these novel oncogenic targets.

描述（申请人提供）：癌症是美国第二大死亡原因，仅次于心脏病，约占所有死亡人数的23%。尽管在许多癌症的治疗方面已经取得了显著的进展，但据估计，在2010年，569，490名美国人将死于这些疾病（Cancer Facts and Figures 2010，American Cancer Society），并且对于许多形式的癌症还没有有效的治疗方法。 癌症的分子复杂性使得鉴定其他致癌途径对治疗干预至关重要。2010年6月，NIH发布了一项计划公告，（PA-10- 213）开发用于探针和治疗前发现的高通量筛选测定法，以鼓励开发新的、科学上杰出的测定法，这些测定法有可能开发成相关的高通量筛选（HTS），高优先级的疾病靶标，用于鉴定小分子工具和治疗候选物。 总之，我们和我们的合作者提供的数据提供了令人信服的证据表明，抑制细胞粘连素，鸟嘌呤核苷酸交换因子，激活Arf家族GTP酶，产生抗癌活性在非常不同的细胞谱系。此外，我们证明，这种抑制作用降低了Ras/Raf/ERK组成性激活的背景下，在体外增殖和侵袭。受体酪氨酸激酶信号通路的这些下游组分的突变极大地限制了目前可用的癌症疗法的效用和有效性。因此，我们相信靶向细胞粘连素ARNO及其效应子Arf 6可能产生有希望的新的小分子抑制剂，可用于对抗先天性和获得性化疗耐药性。 在本申请中，我们寻求具体解决NIH定义的需求，并提出了一种策略，以开发适合HTS活动的测定法，用于鉴定和评估ARNO和/或Arf 6负调节剂。如果成功，我们将寻求通过与NIH最近推出的分子图书馆和成像计划或其他能够访问大型，多样化化合物图书馆的机构合作来自动化这些筛选。从长远来看，这一策略有望确定新的小分子探针和针对这些新的致癌靶点的预治疗化合物。