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

Molecular cancer therapy targeting HuR-ARE interaction

针对 HuR-ARE 相互作用的分子癌症治疗

基本信息

批准号：
9297260
负责人：
Jeffrey Aube
金额：
$ 43.2万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
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：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9297260
关键词：
5&apos Untranslated Regions Adenine Apoptosis Apoptotic BCL2 gene BIRC4 gene Binding Biological Assay Cancer Cell Growth Cell Cycle Progression Cell Line Cell Proliferation Cell Survival Cells Chemicals Data Development Dose Drug Kinetics Drug resistance Elements Embryo Family Fluorescence Polarization Gene Targeting Genetic Translation Histone Deacetylase HuR protein Human In Vitro Inhibition of Apoptosis Knock-in Lead Malignant Neoplasms Maximum Tolerated Dose Messenger RNA Modeling Molecular Mus NOD/SCID mouse Neoplasm Metastasis Normal Cell Notch and Wnt Signaling Pathway Nuclear Magnetic Resonance Oncogenic Pharmaceutical Chemistry Pharmaceutical Preparations Phenocopy Phenotype Proteins RNA RNA-Binding Proteins RNA-Protein Interaction Regulation Resistance Role Series Signal Transduction Structure Structure-Activity Relationship Surface Plasmon Resonance Testing Therapeutic Translations Uridine Validation Vision WNT Signaling Pathway X-Ray Crystallography Xenograft Model angiogenesis anticancer activity base cancer cell cancer initiation cancer stem cell cancer therapy chemotherapy counterscreen cytotoxicity design drug development drug discovery efficacy study experimental study high throughput screening in vivo knock-down mRNA Stability member molecular targeted therapies neoplastic cell notch protein novel novel therapeutics overexpression preclinical study public health relevance self-renewal small molecule success targeted cancer therapy therapy resistant tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The RNA-binding protein Hu antigen R (HuR) is a member of the embryonic lethal abnormal vision (ELAV) family that binds to adenine- and uridine-rich elements (ARE) located in the 3'- or 5'-untranslated region (UTR) of target mRNAs. HuR is overexpressed in a wide variety of cancer, promotes tumorigenesis by interacting with a subset of oncogenic mRNAs implicated in tumor cell proliferation, survival, angiogenesis, invasion, and metastasis. HuR up-regulates the oncogenic Musashi-1/-2 (Msi1/2) and anti-apoptotic proteins, Bcl-2 and XIAP, via binding to AREs and promoting mRNA stability and translation, thus leading to activation of Wnt/Notch signaling pathways and inhibition of apoptosis. These HuR target genes are also involved in cancer stem cell signaling and drug resistance. These findings suggest that HuR is an attractive target for developing novel cancer therapy. So far there is limited success in small molecules that directly inhibit the HuR-RNA interaction. RNA-binding proteins are considered "undruggable" due to the lack of a well-defined binding pocket for target RNA. Through high throughput screening, we have obtained hits that inhibit HuR at nM to µM Ki values, validated by ALPHA, Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) assays. We hypothesize that small molecules that directly disrupt the HuR-ARE interaction, or HuR-ARE disruptors, will block HuR function, leading to modulation of target genes that are critical for cancer cell growth and progression. Our objective is to obtain a series of small molecule compounds that potently bind to HuR and modulate its functions, and ultimately select 1-2 most drug-like lead compounds for further development as a new class of molecular cancer therapy that inhibit cancer with HuR overexpression. Three Specific Aims are proposed: AIM 1, Structure-based rational design and lead optimization of HuR-ARE disruptors; AIM 2, In vitro anti-tumor activity, target validation, and mechanism of action (MOA) studies; AIM 3, In vivo efficacy studies of the lead HuR-ARE disruptors in xenograft models of human cancer, including orthotopic tumor models. Overall Impact: Successfully carried out, this project will discover novel chemical probes for HuR and potentially lead compounds as HuR-ARE disruptors that inhibit cancer cells with high levels of HuR-Notch/Wnt signaling. Discovery of such HuR-ARE disruptors will: (1) provide potent and specific chemical probes for delineating the functional roles of HuR-Msi1-Notch/Wnt signaling in cancer initiation and progression; and (2) provide promising lead compounds to develop novel molecular therapeutics targeting the oncogenic HuR. The data and leads obtained will enable us to seek out partners for further drug discovery and development studies. After assessing structure-activity relationships (SAR) and lead optimization, we may obtain a few lead compounds for further development as a whole new class of molecular cancer therapeutics that inhibit specific protein/RNA interactions required for cancer cell survival and progression.