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（由申请人提供）：癌症是美国第二大死亡原因，仅次于心脏病，约占所有死亡的 23%。尽管许多癌症的治疗已取得重大进展，但预计 2010 年将有 569,490 名美国人死于这些疾病（2010 年癌症事实和数字，美国癌症协会），而且许多癌症尚无有效的治疗方法。 癌症的分子复杂性使得确定适合治疗干预的其他致癌途径至关重要。 2010 年 6 月，NIH 发布了一项关于开发用于探针和治疗前发现的高通量筛选测定的计划公告 (PA-10-213)，以鼓励开发新颖的、科学上出色的测定，这些测定有可能开发成相关、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候选治疗药物。 我们和我们的合作者共同提供的数据提供了令人信服的证据，证明细胞粘附素（激活 Arf 家族 GTP 酶的鸟嘌呤核苷酸交换因子）的抑制可在截然不同的细胞谱系中产生抗癌活性。此外，我们证明这种抑制可减少 Ras/Raf/ERK 组成型激活背景下的体外增殖和侵袭。受体酪氨酸激酶信号通路的这些下游成分的突变极大地限制了当前可用的癌症疗法的实用性和有效性。因此，我们相信靶向细胞粘附素 ARNO 及其效应子 Arf6 可能会产生有前景的新型小分子抑制剂，可用于对抗先天性和获得性化疗耐药性。 在此应用中，我们寻求专门解决 NIH 定义的需求，并提出一种策略来开发适合 HTS 活动的检测方法，旨在识别和评估 ARNO 和/或 Arf6 负调节剂。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库和成像计划或其他能够访问大型、多样化化合物库的机构合作，寻求自动化这些筛选。从长远来看，该策略有望针对这些新的致癌靶点识别新的小分子探针和治疗前化合物。