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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：
8088072
负责人：
Emmanuelle Joelle Meuillet
金额：
$ 34.03万
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/8088072
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 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 Goals Homology Modeling Human In Vitro Inflammation Inflammation Process Inflammatory Interleukins Lead Libraries Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Membrane Metabolic Modeling Molecular Molecular Models Molecular Target Mus Oral Oral mucous membrane structure 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 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 malignant stomach 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重要作用，抑制PGE2的合成为抑制癌细胞生长提供了一种有吸引力的方法。到目前为止，大多数研究都集中在抑制环氧合酶-2(COX-2)上。虽然COX-2抑制剂已经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，在癌症中选择性抑制PGE2合成的替代方法是必要的。前列腺素E_2合成的最后一步是由前列腺素E_2合成酶(PGE_2)控制的，PGE_2合成酶将前列腺素H_2异构化为前列腺素E_2。MPGES的两种微体亚型(mPGES-1和mPGES-2)和一种胞质亚型(cPGES-3)已被鉴定。MPGES-1在许多癌症中过度表达，导致PGE2水平升高，而被设计为过度表达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是抑制PGE2生物合成和抑制肿瘤生长的一个有吸引力的分子靶点。我们使用了mPGES-1的结构同源模型和来自化学库的化学实体的对接模拟来鉴定mPGES-1的新的铅抑制剂。这些化合物在癌细胞中表现出高纳米摩尔范围的活性，没有偏离靶点的COX-2活性，并且在结肠癌细胞异种移植中具有良好的抗肿瘤活性。我们的研究目标是1)开展mPGES-1在肿瘤和炎性间质中参与结肠癌发生发展的分子机制研究；2)利用合理的结构设计，寻找新型、有效、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、确保选择性和无心脏毒性；2)传递类药物性质并在体外测试筛选出的活性类似物，为其生物活性提供机制基础；4)在两个炎症性结肠癌体内模型中测试其中两个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。公共卫生相关性：这项拨款申请的目的是开发针对结肠癌mPGES-1的新型抑制剂。最近的研究表明，这种过度表达的蛋白质可能是治疗结肠癌的良好靶点。我们已经确定了用于硅胶筛选、分子建模和合理药物设计的新化合物，以及三氯生，一种用于牙科的著名化学物质，具有抗炎特性，作为药效团。我们建议进一步开发这些化合物，并在结肠癌细胞系以及存在炎症成分的异种移植和结肠癌动物模型中发现新的线索。我们还将在原位动物模型中研究mPGES-1在间质和肿瘤中的表达和活性的作用。