LRH-1: Structure-based Approach to Drug Design for Gastrointestinal Tumors

LRH-1：基于结构的胃肠道肿瘤药物设计方法

• 批准号: 8460183
• 负责人: James Bayrer
• 金额: $ 1.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460183
• 关键词: Adenomatous Polyposis Coli; Adult; Affect; Affinity; Age; Animal Model; Basic Science; Bile Acids; Binding; Binding Sites; Biochemistry; Biological Assay; Biology; Cancer Etiology; Cell Proliferation; Cell model; Cells; Cellular Assay; Cessation of life; Child; Cholesterol Homeostasis; Clinical; Collaborations; Colon; Colon Carcinoma; Complex; Crystallization; Development; Disease; Drug Design; Eligibility Determination; Erinaceidae; Ethnic Origin; Family; Future; Gastrointestinal Neoplasms; Gene Targeting; Goals; Growth; Hand; Holly; Hormones; Individual; Intestinal Cancer; Intestinal Neoplasms; Intestines; Laboratories; Lead; Ligand Binding; Ligand Binding Domain; Ligands; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medical; Messenger RNA; Metabolism; Methods; Molecular Conformation; Morbidity - disease rate; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Organogenesis; Pancreas; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Preparation; Primary carcinoma of the liver cells; Research; Resolution; Role; Scanning; Series; Specificity; Stomach; Structure; Surface Plasmon Resonance; Techniques; Technology; Temperature; Therapeutic Agents; Tumor Burden; United States; Work; X-Ray Crystallography; alpha helix; base; cancer cell; colon cancer cell line; combinatorial chemistry; design; drug development; drug discovery; experience; gastrointestinal system; genetic regulatory protein; genome wide association study; human NR5A2 protein; in vivo; inhibitor/antagonist; insight; intestinal homeostasis; mortality; mouse model; multidisciplinary; novel; outcome forecast; pancreatic cancer cells; protein structure; receptor; research study; small molecule; tool; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic cancer affects over 40,000 people in the United States each year and worldwide hepatocellular carcinoma (HCC) affects over 600,000 individuals, making it the third leading cause of cancer deaths. Recent evidence points to a role for LRH-1 in intestinal tumorigenesis found in Familial Adenomatous Polyposis (FAP), a condition affecting up to 1 in 7000 individuals. None of these cancers have directed, specific medical therapies, and all carry significant morbidity and mortality. New insight has recently been gained into their pathogenesis: a genome-wide association study identified eight SNPs, five of which localized to the chromosomal region of Liver Receptor Homolog-1 (LRH-1). This orphan nuclear receptor has also been shown to be active in cell proliferation via the Wnt/ -catenin and PDX-1 hedgehog pathways, which are active in the tumorigenesis of HCC and pancreatic cancer. Reduction of LRH-1 has been shown to reduce tumor burden in mouse models of FAP, and mRNA silencing of LRH-1 reduces pancreatic cancer cell proliferation. The central role of LRH-1 in gastroenterological cancer pathogenesis makes it an attractive target for novel drug discovery. Apart from the newly defined role of tumorigenesis, LRH-1 has critical roles in the embryological development of the gastrointestinal system including gut, liver, and pancreas as well as important roles in bile acid and cholesterol homeostasis. Understanding of LRH-1 function is fundamental to future research in organogenesis, tumorigenesis, and gastrointestinal homeostasis. This work proposes to develop and characterize specific, non-cytotoxic inhibitors of LRH-1 function for use as both potential therapeutic agents and more broadly as research tools for the study of organogenesis and tumorigenesis. These Aims will be accomplished via novel cell-based assays designed to investigate inhibitor function within a cellular context as well as established methods of X-ray crystallography of LRH-1: inhibitor complexes and inhibitor binding assays utilizing Differential Scanning Fluorimetry (DSF) and surface Plasmon resonance (SPR) technology. The constructs and techniques are currently in place in the sponsor's laboratory, making the proposed Aims immediately feasible. Novel LRH-1 inhibitors developed in this proposal have the potential to transform the management of some of the most devastating cancers affecting children and adults alike. In addition to the clinical implications, the inhibitors developed in this study will provide tools for basic science research f LRH-1 mediated development and pathogenesis in cell and animal models and provide a basis for development of my K08 application.

描述（由申请人提供）：胰腺癌每年在美国影响40,000多人，全球肝细胞癌（HCC）影响了60万多人，这使其成为癌症死亡的第三大主要原因。最近的证据表明，LRH-1在家族性腺瘤性息肉病（FAP）中发现的肠道肿瘤发生中的作用，这是一种影响7000名患者中有1个的疾病。这些癌症都没有指示特定的医疗疗法，并且都具有明显的发病率和死亡率。最近获得了新的见解：一项全基因组关联研究确定了八个SNP，其中五个定位于肝受体同源物-1的染色体区域（LRH-1）。该孤儿核受体也已被证明通过Wnt/ -Catenin和PDX -1 Hedgehog途径在细胞增殖中活跃，这些途径活跃于HCC和胰腺癌的肿瘤发生中。已显示LRH-1的减少可减轻FAP小鼠模型中的肿瘤负担，而LRH-1的mRNA沉默可减少胰腺癌细胞的增殖。 LRH-1在胃肠癌癌症发病机理中的核心作用使其成为新型药物发现的吸引力。除了新定义的肿瘤发生作用外，LRH-1在胃肠道系统的胚胎学发展中具有关键作用，包括肠道，肝脏和胰腺以及在胆汁酸和胆固醇稳态中的重要作用。对LRH-1功能的理解是器官发生，肿瘤发生和胃肠道稳态的未来研究的基础。这项工作提议开发和表征LRH-1功能的特定，非胞毒性抑制剂作为潜在的治疗剂，并且更广泛地用作研究器官发生和肿瘤发生的研究工具。这些目标将通过基于新颖的细胞测定方法来实现，旨在在细胞环境中研究抑制剂功能，以及使用差异扫描荧光（DSF）和表面等离子体共振（SPR）技术的LRH-1：LRH-1：抑制剂复合物和抑制剂结合测定的X射线晶体学方法。当前，在赞助商的实验室中，这些结构和技术已就位，这使得拟议的目标立即可行。该提案中开发出的新型LRH-1抑制剂有可能改变影响儿童和成人的一些最具破坏性的癌症的管理。除临床意义外，本研究中开发的抑制剂还将为基础科学研究F LRH-1介导的细胞和动物模型中介导的发育和发病机理，并为我的K08应用的开发提供了基础。