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Inhibitors of NAD-Dependent 15-Hydroxyprostaglandin Dehydrogenase for the Study of Prostaglandin's Role in Inflammation

15-hydroxyprostaglandin dehydrogenase (15-PGDH; HPGD) is the key enzyme for the inactivation of prostaglandins, and thus regulates processes such as inflammation or proliferation. The anabolic pathways of prostaglandins are well-characterized, especially with respect to regulation of the cyclooxygenase (COX) enzymes. In comparison, little is known about downstream events, including functional interaction of prostaglandin-processing and metabolizing enzymes, as well as the function of prostaglandin receptors.

Structure of ML147, ML148, and ML149

To date, the only known strong inhibitors belong to the family of thiazolinedines that affect other pathways, notably by binding to peroxisome proliferator-activated receptor (PPAR)³. The present study discloses the discovery and characterization of a potent and competitive HPGD inhibitor that is selective within the dehydrogenase family, ML147 (CID-3245059). It also discloses two high-affinity and uncompetitive HPGD inhibitors that are selective within the dehydrogenase family, ML148 (CID-3243760) and ML149 (CID-2331284). These small molecule probes represent the most potent and selective inhibitors of 15-HPGD reported thus far.

Lead Collaborators

National Center for Advancing Translational Sciences
Ajit Jadhav
Lena Schultz
Craig Thomas, Ph.D.
Damien Duveau, Ph.D.
David J. Maloney, Ph.D.
Anton Simeonov, Ph.D.

Structural Genomics Consortium, University of Oxford, UK
Udo Oppermann, Ph.D.
Frank H. Niesen, Ph.D.

Public Health Impact

The chemical probe compound developed in this project serves as a starting point for drug development in inflammation therapeutics. Inhibition of 15-HPGD has been implicated as a viable target for the treatment of a variety of disorders, including dermal wound healing, bone formation and hair loss. In contrast, down-regulation of HPGD has been linked to increased incidence of several cancers, implying the potential value of HPGD activators in the treatment of cancer.

Publication

Nielsen FH, Schultz L, Jadhav A, et al. High affinity inhibitors of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase: mechanism of inhibition and structure-activity relationships. PLoS ONE, 2010;5(11):e13719.