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（由申请人提供）：RNA 结合蛋白 Hu 抗原 R (HuR) 是胚胎致死性视力异常 (ELAV) 家族的成员，与位于 3'- 的富含腺嘌呤和尿苷的元件 (ARE) 结合靶 mRNA 的 5'-非翻译区 (UTR) 在多种癌症中过度表达，通过与肿瘤中涉及的致癌 mRNA 子集相互作用来促进肿瘤发生。 HuR 通过与 ARE 结合并促进 mRNA 稳定性，上调致癌 Musashi-1/-2 (Msi1/2) 和抗凋亡蛋白 Bcl-2 和 XIAP。这些 HuR 靶基因还参与癌症干细胞信号传导和耐药性。迄今为止，由于缺乏明确的靶RNA结合口袋，直接抑制HuR-RNA相互作用的小分子取得的成功有限。，我们获得了在 nM 至 µM Ki 值范围内抑制 HuR 的命中结果，并通过 ALPHA、表面等离子共振 (SPR) 和核磁共振 (NMR) 测定进行了验证，我们捕获了直接破坏 HuR 的小分子。 HuR-ARE 相互作用或 HuR-ARE 干扰物将阻断 HuR 功能，从而调节对癌细胞生长和进展至关重要的靶基因。我们的目标是获得一系列有效结合 HuR 并调节的小分子化合物。其功能，并最终选择 1-2 个最类似药物的先导化合物进行进一步的化合物开发，作为抑制 HuR 过度表达的癌症的新型分子癌症疗法。提出了三个具体目标：AIM 1、基于结构的合理设计和先导化合物优化。 HuR-ARE 干扰剂的研究；AIM 2，体外抗肿瘤活性、靶点验证和作用机制 (MOA) 研究；AIM 3，主要 HuR-ARE 干扰剂在人类癌症异种移植模型中的体内功效研究；原位肿瘤模型。总体影响：成功实施后，该项目将发现 HuR 的新型化学探针，以及作为 HuR-ARE 干扰物的潜在先导化合物，可抑制高水平的癌细胞。 HuR-Notch/Wnt 信号传导。此类 HuR-ARE 干扰物的发现将：（1）提供有效且特异性的化学探针，用于描述 HuR-Msi1-Notch/Wnt 信号传导在癌症发生和进展中的功能作用；有前景的先导化合物可用于开发针对致癌 HuR 的新型分子疗法。获得的数据和先导化合物将使我们能够寻找合作伙伴进行进一步的药物发现和开发研究。在评估构效关系 (SAR) 和先导化合物优化后，我们可能会获得。一些先导化合物将进一步开发为一类全新的分子癌症疗法，抑制癌细胞生存和进展所需的特定蛋白质/RNA 相互作用。