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: 8544183
• 负责人: DEAN Yaw LI
• 金额: $ 28.64万
• 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/8544183
• 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（由申请人提供）：癌症是美国第二大死亡原因，仅次于心脏疾病，约占总死亡人数的23%。尽管在治疗许多癌症方面取得了重大进展，但据估计，2010年将有569,490名美国人死于这些疾病（2010年癌症事实和数据，美国癌症协会），而且对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别其他的致癌途径对治疗干预是至关重要的。2010年6月，美国国立卫生研究院发布了一项项目公告（PA-10- 213），用于开发用于探针和治疗前发现的高通量筛选检测方法，以鼓励开发新的、科学上杰出的检测方法，这些检测方法有可能发展成相关的、高优先级疾病靶点的高通量筛选（HTS），用于识别小分子工具和治疗候选药物。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，证明抑制细胞分裂素（激活Arf家族gtpase的鸟嘌呤核苷酸交换因子）在不同的细胞系中产生抗癌活性。此外，我们证明了这种抑制在Ras/Raf/ERK组成激活的背景下减少了体外增殖和侵袭。这些受体酪氨酸激酶信号通路下游组分的突变极大地限制了目前可用的癌症治疗的效用和有效性。因此，我们相信靶向细胞分裂素ARNO及其效应物Arf6可能会产生新的小分子抑制剂，用于对抗先天和获得性化疗耐药。在本申请中，我们寻求具体解决NIH定义的需求，并提出一项战略，以开发适合HTS活动的测定方法，用于鉴定和评估ARNO和/或Arf6阴性调节剂。如果成功，我们将通过与美国国立卫生研究院最近启动的分子文库和成像计划或其他可以访问大型、多样化化合物文库的机构合作，寻求自动化这些筛选。从长远来看，这一策略有望识别出新的小分子探针和治疗前化合物来对抗这些新的致癌靶点。