Inhibitors of 12-Human Lipoxygenase for the Treatment of Diabetes and Clotting
Human lipoxygenases (hLOs) are distributed among a variety of tissues and cellular locations in the body, and they are part of the first committed step in a cascade of metabolic pathways. As such, hLOs are implicated in the onset of inflammatory diseases such as cancers, heart disease and asthmas, making them an ideal target for pharmaceutical intervention. The lipoxygenase platelet-type 12-(S)-hLO has been implicated in skin diseases, diabetes, platelet hemostasis, thrombosis and cancer. Despite the potential of 12-hLO as a therapeutic target, potent and selective inhibitors of the enzyme are lacking in the patent or public literature.
To date, the only known modulators of 12-hLO are either weak inhibitors or promiscuous polyphenolic compounds that inhibit several of the closely related isoymes. In this report, we describe the development of small-molecule inhibitors that exhibit nanomolar potency against 12-hLO and >50-fold selectivity over the related lipoxygenases and cyclooxygneases. Kinetic experiments indicate that this chemotype is a non-competitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of several of the racemic lead molecules revealed a strong preference for the (-)-enantiomer (IC50 ~ 0.4µM) compared to > 25µM for the (+)-enantiomer, indicating a fine degree of selectivity in the active site due to chiral geometry. The small molecule probe ML127 (CID 44460175) and its related analogs represent the most potent and selective 12-hLO inhibitors reported thus far.
National Center for Advancing Translational Sciences
Ganesha Rai, Ph.D.
Anton Simeonov, Ph.D.
David J. Maloney, Ph.D.
University of California, Santa Cruz
Theodore R. Holman, Ph.D.
Victor Kenyon, Ph.D.
Public Health Impact
Diabetes affects upwards of 25.8 million children and adults in United States, with medical expenditures totaling several hundred billions of dollars. The characterized probe compound will be useful as a tool to study the biological role of 12-hLO in lipid- and prostaglandin-mediated signaling as related to progression of type 1 diabetes as well as inflammation, human platelet reactivity, clot formation, and cancer.
Rai G, Kenyon V, Jadhav A, et al. Discovery of potent and selective inhibitors of human reticulocyte 15-lipoxygenase-1. J Med Chem, 2010;53:7392-7404.