Identification and development of inhibitors of the Hippo-Yap pathway

Hippo-Yap 途径抑制剂的鉴定和开发

• 批准号: 9036349
• 负责人: JOSEPH KISSIL
• 金额: $ 43.92万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-17 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036349
• 关键词: Antineoplastic Agents; Apoptotic; Automobile Driving; Binding; Biochemical; Biological Assay; Cell Survival; Cells; Clinical; Colorectal; Colorectal Cancer; Cytoplasm; Development; Disabled Persons; Distal; Epigenetic Process; Event; GNAQ gene; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Lead; Libraries; Liver; Luciferases; Malignant Neoplasms; Malignant neoplasm of liver; Mammals; Mesothelioma; Miniaturization; Modeling; Molecular; Neoplasm Metastasis; Neurilemmoma; Neurofibromatosis 2; Oncogenes; Organ Size; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Primary carcinoma of the liver cells; Property; Proteins; Reporter; Research; Series; Signal Pathway; Squamous cell carcinoma; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transcription Coactivator; Tumor Suppressor Genes; Uveal Melanoma; Validation; analog; base; cancer therapy; cancer type; cell growth; drug discovery; gene function; high throughput screening; in vivo; inhibitor/antagonist; malignant breast neoplasm; melanoma; meningioma; miniaturize; neoplastic cell; novel; pharmacophore; protein function; safety testing; screening; small molecule inhibitor; transcription factor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): The Hippo-YAP signaling pathway has emerged as a major driver of tumorigenesis and metastasis in a wide spectrum of human malignancies. The distal effector of the pathway - YAP, functions as a transcriptional activator driving expression of pro-proliferation and anti- apoptotic genes. Importantly, several tumor types are YAP dependent, including colorectal, hepatocellular, meningioma, mesothelioma and schwannoma. Several studies strongly promote the notion that inhibiting the Hippo-YP pathway will show efficacy in a broad spectrum of cancer types. Our long-term goal is to identify small molecule inhibitors of the Hippo-Yap pathway that can be developed into therapeutic agents for the treatment of cancers that are Hippo- YAP dependent. To obtain potent lead compounds that selectively inhibit YAP-driven transcription we will implement an ultra High Throughput Screening campaign using the Scripps Drug Discovery Library. Identified leads will assessed in a series of secondary screens and Structure Activity Relationship analysis and medicinal chemistry will be used to optimize and prioritize leads based on their drug-like properties. Top leads will be used in mechanism of action studies and tested in cell-based models of YAP-dependent tumors including meningioma and schwannoma cells to determine the effects of select compounds on tumor cell growth and survival. The proposed research campaign will identify safe and potent lead compounds that will be tested in vivo and leads suitable for clinical development as therapeutics will be identified. These studies should result in identification of select leads demonstrating efficacy against a broad spectrum of human tumors which are YAP-dependent involvement.

 描述（由申请人提供）：Hippo-YAP信号通路已成为多种人类恶性肿瘤中肿瘤发生和转移的主要驱动因素。该途径的远端效应物-雅普，作为转录激活物起作用，驱动促增殖和抗凋亡基因的表达。重要的是，几种肿瘤类型是雅普依赖性的，包括结直肠癌、肝细胞癌、脑膜瘤、间皮瘤和神经鞘瘤。几项研究强烈提倡抑制Hippo-YP通路将在广泛的癌症类型中显示功效的概念。我们的长期目标是鉴定Hippo-雅普途径的小分子抑制剂，其可以被开发成用于治疗Hippo-雅普依赖性癌症的治疗剂。为了获得选择性抑制YAP驱动的转录的有效先导化合物，我们将使用Scripps药物发现库实施超高重复率筛选活动。将在一系列二次筛选中评估已识别的先导化合物，并将使用结构活性关系分析和药物化学根据其药物样性质优化和优先考虑先导化合物。顶级先导化合物将用于作用机制研究，并在YAP依赖性肿瘤（包括脑膜瘤和神经鞘瘤细胞）的细胞模型中进行测试，以确定所选化合物对肿瘤细胞生长和存活的影响。拟议的研究活动将确定安全和有效的先导化合物，这些化合物将在体内进行测试，并适用于临床 将确定作为治疗剂的开发。这些研究应导致确定选择的线索，证明对YAP依赖性参与的广谱人类肿瘤的疗效。