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：
8964473
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/8964473
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 Mouse 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 X-Ray Crystallography Xenograft Model angiogenesis anticancer activity base cancer cell cancer initiation cancer stem cell cancer therapy chemotherapy cytotoxicity design drug development drug discovery high throughput screening in vivo knock-down mRNA Stability member neoplastic cell notch protein novel overexpression preclinical study public health relevance research study self-renewal small molecule success targeted cancer therapy targeted treatment therapeutic target 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.

描述（由适用提供）：RNA结合蛋白Hu抗原R（HUR）是与位于3'-或5'-非固定型腺嘌呤或5'-非反发质区域（UTR）目标mRNA的胚胎致死异常视力（ELAV）家族的成员。 HUR在多种癌症中过表达，通过与在肿瘤细胞增殖，生存，血管生成，侵袭和转移中实施的致癌mRNA相互作用来促进肿瘤发生。 HUR通过与ARES结合并促进mRNA稳定性和翻译，从而上调致癌的Musashi-1/-2（MSI1/2）和抗凋亡蛋白Bcl-2和XIAP，从而导致Wnt/Notch信号通路和凋亡抑制。这些HUR靶基因也参与癌症干细胞信号传导和耐药性。这些发现表明，HUR是开发新型癌症治疗的有吸引力的靶标。到目前为止，在直接抑制HUR-RNA相互作用的小分子中取得了有限的成功。由于缺乏针对靶RNA的定义明确的结合袋，RNA结合蛋白被认为是“不可能”的。通过高吞吐量筛选，我们获得了抑制NM至µm ki值的命中，并通过Alpha，表面等离子体共振（SPR）和核磁共振（NMR）测定验证。我们假设直接破坏HUR-ARE相互作用或HUR-ARE破坏者的小分子将阻止HUR功能，从而导致对靶基因的调节，这对癌细胞生长和进展至关重要。我们的目标是获得一系列潜在结合HUR并调节其功能的小分子化合物，并最终选择1-2个最类似药物的铅化合物，以作为一种新的分子癌疗法作为一种新的分子癌疗法，从而抑制HUR过表达的癌症。提出了三个具体目标：AIM 1，基于结构的理性设计和HUR-ARE破坏者的铅优化； AIM 2，体外抗肿瘤活性，目标验证和作用机理（MOA）研究； AIM 3，在人类癌症的异种移植模型（包括原位肿瘤模型）中对铅HUR-ARE破坏者的体内效率研究。总体影响：成功进行的，该项目将发现HUR的新化学问题，并可能将铅化合物作为HUR-ARE颠覆器，抑制高水平的HUR-NOTCH/WNT信号传导的癌细胞。此类HUR-ARE破坏者的发现将：（1）提供了描述HUR-MSI1-NOTCH/WNT信号在癌症开始和进展中的功能作用的潜在和特定的化学问题；（2）为开发针对致癌性HUR的新型分子疗法提供了有望的领先化合物。获得的数据和潜在客户将使我们能够寻求伴侣进行进一步的药物发现和开发研究。在评估了结构活性关系（SAR）和铅优化之后，我们可能会获得一些铅化合物，以进一步发展，这是一类全新的分子癌治疗，抑制癌细胞存活和进展所需的特定蛋白质/RNA相互作用。