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Inhibition of novel molecular targets of prostaglandin formation for antitumor ac

抑制前列腺素形成的新分子靶点抗肿瘤活性

基本信息

批准号：
7985087
负责人：
Emmanuelle Joelle Meuillet
金额：
$ 35.58万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7985087
关键词：
Affect Anabolism Animal Model Animals Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Applications Grants Arachidonic Acids Binding Biological Blood Pressure Brain Breast Cancer Cell Growth Cardiotoxicity Catalytic Domain Cells Chemicals Colon Colon Carcinoma Colonic Neoplasms Computer Simulation Computing Methodologies Coxibs Dentistry Development Dinoprostone Docking Dose Drug Design Eicosanoids Engineering Enzymes Epoprostenol Exhibits Future Gene Deletion Genes Genus Cola Goals Homology Modeling Human In Vitro Inflammation Inflammation Process Inflammatory Interleukins Lead Libraries Lung Malignant Neoplasms Malignant neoplasm of prostate Membrane Metabolic Modeling Molecular Molecular Models Molecular Target Mus Oral Oral mucous membrane structure Pancreas Pharmaceutical Preparations Phenols Phospholipase A2 Phospholipids Play Preparation Process Production Property Prostaglandin Endoperoxides Prostaglandin H2 Prostaglandin Inhibition Prostaglandins Protein Isoforms Proteins Regulation Role Spectrum Analysis Stomach Structure Study models Surface Plasmon Resonance Testing Triclosan Tumorigenicity Uncertainty Validation Work Xenograft procedure analog base cancer cell cancer initiation carcinogenesis cellular engineering colon cancer cell line cyclooxygenase 2 design drug development improved in vivo in vivo Model inhibitor/antagonist malignant breast neoplasm molecular modeling mouse PGE synthase 1 mouse model novel novel strategies overexpression pharmacophore public health relevance simulation small molecule small molecule libraries therapeutic target tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Prostaglandin E2 (PGE2) plays an important role in cancer initiation and progression and inhibiting PGE2 synthesis offers an attractive way to inhibit cancer cell growth. Most studies to date have focused on inhibiting cyclooxygenase-2 (COX-2). While COX-2 inhibitors have shown anti-tumor activity animals and humans, the occurrence of cardiotoxicity associated with the use of high doses of COX-2 inhibitors has cast doubts as to their future use. Thus, alternative ways of selectively inhibiting PGE2 synthesis in cancer are needed. The final step in PGE2 synthesis is controlled by PGE2 synthases (PGESs) that isomerize PGH2 into PGE2. Two microsomal isoforms for mPGES (mPGES-1 and mPGES-2) and one cytosolic form (cPGES-3) have been identified. mPGES-1 is over-expressed in many cancers leading to increased levels of PGE2 while cells engineered to overexpress mPGES-1 show high levels of tumorigenicity. Deleting mPGES-1 in animals does not give rise to the cardiotoxicity typically associated with the use of COX-2 inhibitors. mPGES-1, thus, represents an attractive molecular target for inhibiting PGE2 biosynthesis and inhibiting tumor growth. We have used a structural homology model of mPGES-1 and docking simulations of chemical entities from chemical libraries to identify novel lead inhibitors of mPGES-1. The compounds exhibit activity in the high nanomolar range in cancer cells, with no off-target COX-2 activity and with promising anti-tumor activity in colon cancer cells xenografts. The objectives of our studies are 1) to conduct molecular mechanistic studies of the role of mPGES-1 in tumor and inflammatory stroma in the development of colon cancer; 2) to identify novel, potent, selective and efficacious inhibitors for mPGES-1 using rational structure-based design; 3) to synthesize focused libraries of analogs to improve biological activity, insure of selectivity and absence of cardiotoxicity; to impart drug like properties and to test select active analogs in vitro to provide a mechanistic rationale for their biological activity and 4) to test the anti-tumor properties of two of the lead compounds in two in vivo models of inflammatory colon cancer. The overall goal of our work is to develop novel agents for the improved treatment of colon cancer. PUBLIC HEALTH RELEVANCE: The purpose of this grant application is to develop novel inhibitors targeting mPGES-1 in colon cancer. Recent studies have suggested that this over-expressed protein may be a good therapeutic target for the treatment of colon cancer. We have identified novel compounds using in silico screens, molecular modeling and rational drug design and Triclosan, a well-known chemical used in dentistry with anti-inflammatory properties as the pharmacophore. We propose to further develop these compounds as well as identify new leads in colon cancer cell lines as well as xenografts and colon cancer animal model in which the inflammation component is present. We also will investigate the role for mPGES-1 expression and activity in stroma and tumor in orthotopic animal models.

描述（申请人提供）：前列腺素E2 （PGE2）在癌症的发生和发展中起着重要作用，抑制PGE2的合成是抑制癌细胞生长的一种有吸引力的方法。迄今为止，大多数研究都集中在抑制环氧化酶-2 （COX-2）上。虽然COX-2抑制剂在动物和人类中显示出抗肿瘤活性，但与使用高剂量COX-2抑制剂相关的心脏毒性的发生使人们对其未来的使用产生了怀疑。因此，需要有选择性地抑制肿瘤中PGE2合成的替代方法。PGE2合成的最后一步是由PGE2合成酶（PGESs）控制的，它将PGH2异构化为PGE2。已经鉴定出mPGES的两种微粒体亚型（mPGES-1和mPGES-2）和一种细胞质亚型（cPGES-3）。mPGES-1在许多癌症中过度表达，导致PGE2水平升高，而经过工程改造过表达mPGES-1的细胞显示出高水平的致瘤性。在动物中删除mPGES-1不会引起通常与使用COX-2抑制剂相关的心脏毒性。因此，mPGES-1代表了抑制PGE2生物合成和抑制肿瘤生长的一个有吸引力的分子靶点。我们利用mPGES-1的结构同源性模型和化学库中化学实体的对接模拟来鉴定mPGES-1的新型先导抑制剂。这些化合物在癌细胞中表现出高纳摩尔范围的活性，没有脱靶COX-2活性，并且在结肠癌细胞异种移植中具有很好的抗肿瘤活性。我们的研究目标是：1)开展mPGES-1在肿瘤和炎症基质中结肠癌发生的分子机制研究；2)通过合理的结构设计，鉴定新型、强效、选择性和有效的mPGES-1抑制剂；3)合成有针对性的类似物文库，以提高生物活性，确保其选择性和无心脏毒性；赋予类似药物的特性，并在体外测试选定的活性类似物，以提供其生物活性的机制基础；4)在两种炎症性结肠癌的体内模型中测试两种先导化合物的抗肿瘤特性。我们工作的总体目标是开发新的药物来改善结肠癌的治疗。