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.
