权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identification and development of inhibitors of the Hippo-Yap pathway

Hippo-Yap 途径抑制剂的鉴定和开发

基本信息

批准号：
9231398
负责人：
JOSEPH KISSIL
金额：
$ 35.14万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
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/9231398
关键词：
Antineoplastic Agents Apoptotic Automobile Driving Binding Biochemical Biological Assay Cell Survival Cells Colorectal Colorectal Cancer Cytoplasm Development Disabled Persons Distal Epigenetic Process Event GNAQ gene Genes Genetic Genetic Transcription Goals 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 Phenotype Phosphorylation Phosphotransferases Primary carcinoma of the liver cells Property Proteins Reporter Research Series Signal Pathway Signaling Protein 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 clinical development counterscreen drug discovery gene function high throughput screening in vivo inhibitor/antagonist malignant breast neoplasm melanoma meningioma miniaturize neoplastic cell novel pharmacophore public health relevance safety testing screening small molecule inhibitor transcription factor tumor tumorigenesis

项目摘要

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.