Inhibition of novel molecular targets of prostaglandin formation for antitumor ac

描述（由申请人提供）：前列腺素E2（PGE 2）在癌症的发生和发展中起重要作用，抑制PGE 2合成提供了一种有吸引力的抑制癌细胞生长的方法。迄今为止，大多数研究都集中在抑制环氧合酶-2（考克斯-2）上。虽然考克斯-2抑制剂在动物和人中显示出抗肿瘤活性，但与使用高剂量的考克斯-2抑制剂相关的心脏毒性的发生对其未来的使用产生了怀疑。因此，需要选择性抑制癌症中PGE 2合成的替代方法。PGE 2合成的最后一步由PGE 2异构化酶（PGES）控制，PGH 2异构化为PGE 2。已鉴定出mPGES的两种微粒体亚型（mPGES-1和mPGES-2）和一种胞质型（cPGES-3）。mPGES-1在许多癌症中过表达，导致PGE 2水平增加，而经工程改造以过表达mPGES-1的细胞显示高水平的致瘤性。在动物中删除mPGES-1不会引起通常与使用考克斯-2抑制剂相关的心脏毒性。因此，mPGES-1代表了用于抑制PGE 2生物合成和抑制肿瘤生长的有吸引力的分子靶标。我们已经使用mPGES-1的结构同源性模型和来自化学文库的化学实体的对接模拟来鉴定mPGES-1的新型先导抑制剂。所述化合物在癌细胞中表现出高纳摩尔范围的活性，没有脱靶考克斯-2活性，并且在结肠癌细胞异种移植物中具有有希望的抗肿瘤活性。我们的研究目的是：1）对mPGES-1在结肠癌发生发展中的肿瘤和炎性基质中的作用进行分子机制研究; 2）使用合理的基于结构的设计来鉴定mPGES-1的新的、强效的、选择性的和有效的抑制剂; 3）合成集中的类似物文库以提高生物活性，确保选择性和无心脏毒性;赋予药物样性质并在体外测试所选择的活性类似物以提供其生物活性的机理原理和4）在两种炎性结肠癌的体内模型中测试两种先导化合物的抗肿瘤性质。我们工作的总体目标是开发用于改善结肠癌治疗的新型药物。 公共卫生相关性：该拨款申请的目的是开发针对结肠癌中mPGES-1的新型抑制剂。最近的研究表明，这种过表达的蛋白可能是治疗结肠癌的良好治疗靶点。我们已经确定了新的化合物，使用计算机屏幕，分子建模和合理的药物设计和三氯生，一个众所周知的化学品用于牙科与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异种移植物和存在炎症成分的结肠癌动物模型中鉴定新的先导化合物。我们还将研究原位动物模型中mPGES-1在基质和肿瘤中的表达和活性的作用。

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.