Cyclooxygenase-2 (COX-2) a promising target for cancer chemoprevention and adjuvant therapy. It is one of two COX enzymes that catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides. The latter are converted to a family of bioactive lipids that regulate a wide range of physiological functions including cell growth, motility, and angiogenesis. COX-2 is the product of an immediate early gene that is rapidly but transiently expressed in epithelial cells in response to an extremely diverse range of stimuli including growth factors, cytokines, and tumor promoters. COX-2 expression in a number of tumors is constitutive and appears to be an early event related to transformation. Targeted deletion of the COX-2 gene or pharmacological inhibition with non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors reduces tumorigenesis. Structure-based functional analysis has provided important insights into the role of individual amino acid residues in substrate binding, inhibitor binding, and catalytic activity. Through such studies, our laboratory discovered that COX-2 binds neutral derivatives (esters and amides) of carboxylic acid-containing NSAIDs much more tightly than COX-1, which provides a facile strategy for converting non-selective NSAIDs into highly selective COX-2 inhibitors. In addition, we discovered that COX-2 selectively utilizes the neutral derivatives of arachidonic acid, 2-arachidonyl glycerol (2-AG) and arachidonyl ethanolamide (AEA) as substrates for production of glyceryl prostaglandins and ethanolamide prostaglandins. 2-AG and AEA are the two known endogenous ligands for the cannabinoid receptors so our discovery provides a link between endocannabinoid signaling and COX-2 action. An growing body of evidence implicates endocannabinoids in the control of tumor growth and metastasis so our discovery may provide important insights into the unique role of COX-2 in tumorigenesis. We propose to conduct a multi- disciplinary and multi-institutional study of the interaction of COX-2 with endocannabinoids and novel COX-2 inhibitors. The studies will include structural analysis of complexes of COX-2 with.substrates and inhibitors, functional analysis of the the role of specific amino acids in these interactions, and kinetic analysis of the dynamics of COX-2-inhjbitor interactions. The results of these investigations will provide fundamental knowledge for understanding the role of COX-2 in a selective signal transduction pathway and for designing COX-2 targeted drugs and imaging agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089450-10
Application #
7740169
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Malone, Winfred F
Project Start
2001-02-08
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
10
Fiscal Year
2010
Total Cost
$417,142
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Adeniji, Adegoke; Uddin, Md Jashim; Zang, Tianzhu et al. (2016) Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. J Med Chem 59:7431-44
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