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.
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.
|Tan, Zhi; Zhang, Shuxing (2016) Past, Present, and Future of Targeting Ras for Cancer Therapies. Mini Rev Med Chem 16:345-57|
|Chen, Lu; Du-Cuny, Lei; Moses, Sylvestor et al. (2015) Novel inhibitors induce large conformational changes of GAB1 pleckstrin homology domain and kill breast cancer cells. PLoS Comput Biol 11:e1004021|
|Reddy, A Srinivas; Tan, Zhi; Zhang, Shuxing (2014) Curation and analysis of multitargeting agents for polypharmacological modeling. J Chem Inf Model 54:2536-43|
|Reddy, A Srinivas; Zhang, Shuxing (2013) Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol 6:41-7|
|Medda, Federico; Sells, Earlphia; Chang, Hui-Hua et al. (2013) Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells. Bioorg Med Chem Lett 23:528-31|
|Nakanishi, Masako; Rosenberg, Daniel W (2013) Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol 35:123-37|
|Norberg, Jessica K; Sells, Earlphia; Chang, Hui-Hua et al. (2013) Targeting inflammation: multiple innovative ways to reduce prostaglandin Eâ‚‚. Pharm Pat Anal 2:265-88|
|Smith, Breland; Chang, Hui-Hua; Medda, Federico et al. (2012) Synthesis and biological activity of 2-aminothiazoles as novel inhibitors of PGE2 production in cells. Bioorg Med Chem Lett 22:3567-70|
|Chang, Hui-Hua; Song, Zuohe; Wisner, Lee et al. (2012) Identification of a novel class of anti-inflammatory compounds with anti-tumor activity in colorectal and lung cancers. Invest New Drugs 30:1865-77|
|Chang, Hui-Hua; Meuillet, Emmanuelle J (2011) Identification and development of mPGES-1 inhibitors: where we are at? Future Med Chem 3:1909-34|
Showing the most recent 10 out of 12 publications