Pre-clinical Developmemt of a Novel COX-2 Inhibitor

描述（由申请方提供）：据报道，考克斯-2的上调发生在癌细胞中，并且在动物模型中已经证明选择性抑制考克斯-2可减少癌细胞生长。此外，大量文献表明，环氧合酶-2（考克斯-2）可能有助于各种类型癌症（包括结肠癌和肺癌）中的癌细胞生长。事实上，许多关于长期使用NSAID的研究已经证明了改善或降低癌症的可能性。选择性考克斯-2不良胃肠道副作用的减少刺激了目前市售的考克斯-2抑制剂用于癌症的长期临床评价研究。我们已经开发了一种新的化学型（Onconova化合物ON 09** 系列），具有有效和选择性的考克斯-2抑制活性。与Dr. E合作。天普大学费尔斯癌症研究所的Premkumar Reddy博士说，这些化合物现在被应用于各种适应症，包括预防癌症和炎症。具体目标如下：短期; 6个月-使用围绕Onconova鉴定的新化学型创建的考克斯-2抑制剂的微型文库，我们将在Dr. Reddy的酶测定模型中评价这些药物对考克斯-2的抑制水平。具体而言，将进行研究以确定这些新型考克斯-2化合物对乳腺癌和结肠癌的治疗潜力。基于这些结果，我们将采用构效关系（SAR）来制备额外的新型考克斯-2化合物用于评价。我们将用我们的新系列化合物建立SAR活性模式。中期-在体外模型中有效证明癌细胞凋亡将有助于鉴定结直肠癌、乳腺癌和前列腺癌体内动物研究中感兴趣的活性化合物。在确定了一种先导化合物之后，将为这些研究生产大量化合物。长期-成功完成第1阶段的候选人将得到进一步发展。第2阶段和第3阶段评估的后续研究将根据公司的需求在内部或与商业合作伙伴进行。

DESCRIPTION (provided by applicant): Up-regulation of COX-2 has been reported to occur in cancer cells and selective inhibition of COX-2 has been demonstrated to reduce cancer cell growth in animal models. In addition, there has been a voluminous literature that suggests that cyclooxygenase-2 (COX-2) may contribute to cancer cell growth in various types of cancer including colon and lung carcinomas. Indeed, numerous studies on the long-term use of NSAIDs have demonstrated the improvement or a decrease in the potential of cancer. The decrease in undesirable GI side effects of selective COX-2 has stimulated long-term clinical evaluation studies of current marketed COX-2 inhibitor for cancer. We have developed a novel chemotype (Onconova compounds ON 09** Series) with potent and selective COX-2 inhibitory activity. In collaboration with Dr. E. Premkumar Reddy, at The Fels Institute for Cancer Research, Temple University, these compounds are now being applied for various indications including prevention of cancer and inflammation. The specific aims are as follows: Short term; 6 months - Employing the mini library of COX-2 inhibitors created around the new chemotype identified by Onconova, we will evaluate the level of inhibition of COX-2 by these drugs in Dr. Reddy's enzymatic assay model. Specifically, studies will be undertaken to determine the therapeutic potential of these novel COX-2 compounds against breast and colon cancer. Based on these results, we will employ Structure Activity Relationship (SAR) to prepare additional novel COX-2 compounds for evaluation. We will establish a SAR pattern of activity with our novel series of compounds. Intermediate term - Effective demonstration of cancer cell apoptosis in the in vitro model will aid in the identification of interesting and active compounds for in vivo animal studies of colorectal, breast and prostate cancer. Following the identification of a lead compound, production of large quantities of the compound for these studies will be undertaken. Long term - A candidate that successfully completes Phase 1 will be further developed. The later studies for Phase 2 and Phase 3 evaluations will be carried out internally or with a commercial partner, based on the needs of the company.