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A high throughput screen identifies potent and selective inhibitors to human epithelial 15-lipoxygenase-2.

Jameson JB, Kantz A, Schultz L, Kalyanaraman C, Jacobson MP, Maloney DJ, Jadhav A, Simeonov A, Holman TR - PLoS ONE (2014)

Bottom Line: MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/-0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2.MLS000536924 is a competitive inhibitor with a Ki of 2.5+/-0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above.Finally, neither compound possesses reductive activity towards the active-site ferrous ion.

View Article: PubMed Central - PubMed

Affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.

ABSTRACT
Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15-lipoxygenase-2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15-LOX-2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15-LOX-2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/-0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a Ki of 2.5+/-0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion.

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Current known 15-LOX-2 inhibitors (IC50 values are in µM).
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pone-0104094-g001: Current known 15-LOX-2 inhibitors (IC50 values are in µM).

Mentions: Given the complex biological role of both 15-LOX-1 and 15-LOX-2, it would be helpful to have specific inhibitors of these two isozymes to better delineate their roles in human disease. Potent and selective inhibitors of 15-LOX-1 have been identified [8]–[12], however, no potent and selective inhibitors for 15-LOX-2 have been observed. There are currently two inhibitors with potency against 15-LOX-2 in the literature (Figure 1). The first, nordihydroguaiaretic acid (NDGA), is a redox active LOX inhibitor and has an IC50 value of 11.0+/−0.7 µM for 15-LOX-2 [13]. The second is the flavanoid based compound, 27c, which has an IC50 value of 8.3+/−0.9 µM [13]. However, neither of these compounds is selective toward 15-LOX-2. Due to this dearth of potent and selective 15-LOX-2 inhibitors, we set out to identify novel inhibitors against 15-LOX-2 using our previously reported high throughput screen [14] that has already yielded potent and selective compounds against 15-LOX-1 [8] and platelet 12-LOX (12-LOX) [15], [16]. In the current work, we report two potent and selective 15-LOX-2 inhibitors that were characterized by kinetic analysis and could be used further to characterize the biological mechanism by which 15-LOX-2 affects disease progression.


A high throughput screen identifies potent and selective inhibitors to human epithelial 15-lipoxygenase-2.

Jameson JB, Kantz A, Schultz L, Kalyanaraman C, Jacobson MP, Maloney DJ, Jadhav A, Simeonov A, Holman TR - PLoS ONE (2014)

Current known 15-LOX-2 inhibitors (IC50 values are in µM).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4128814&req=5

pone-0104094-g001: Current known 15-LOX-2 inhibitors (IC50 values are in µM).
Mentions: Given the complex biological role of both 15-LOX-1 and 15-LOX-2, it would be helpful to have specific inhibitors of these two isozymes to better delineate their roles in human disease. Potent and selective inhibitors of 15-LOX-1 have been identified [8]–[12], however, no potent and selective inhibitors for 15-LOX-2 have been observed. There are currently two inhibitors with potency against 15-LOX-2 in the literature (Figure 1). The first, nordihydroguaiaretic acid (NDGA), is a redox active LOX inhibitor and has an IC50 value of 11.0+/−0.7 µM for 15-LOX-2 [13]. The second is the flavanoid based compound, 27c, which has an IC50 value of 8.3+/−0.9 µM [13]. However, neither of these compounds is selective toward 15-LOX-2. Due to this dearth of potent and selective 15-LOX-2 inhibitors, we set out to identify novel inhibitors against 15-LOX-2 using our previously reported high throughput screen [14] that has already yielded potent and selective compounds against 15-LOX-1 [8] and platelet 12-LOX (12-LOX) [15], [16]. In the current work, we report two potent and selective 15-LOX-2 inhibitors that were characterized by kinetic analysis and could be used further to characterize the biological mechanism by which 15-LOX-2 affects disease progression.

Bottom Line: MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/-0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2.MLS000536924 is a competitive inhibitor with a Ki of 2.5+/-0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above.Finally, neither compound possesses reductive activity towards the active-site ferrous ion.

View Article: PubMed Central - PubMed

Affiliation: Chemistry and Biochemistry Department, University of California Santa Cruz, Santa Cruz, California, United States of America.

ABSTRACT
Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic acids with varying positional specificity to yield important biological signaling molecules. Human epithelial 15-lipoxygenase-2 (15-LOX-2) is a highly specific LOX isozyme that is expressed in epithelial tissue and whose activity has been correlated with suppression of tumor growth in prostate and other epithelial derived cancers. Despite the potential utility of an inhibitor to probe the specific role of 15-LOX-2 in tumor progression, no such potent/specific 15-LOX-2 inhibitors have been reported to date. This study employs high throughput screening to identify two novel, specific 15-LOX-2 inhibitors. MLS000545091 is a mixed-type inhibitor of 15-LOX-2 with a Ki of 0.9+/-0.4 µM and has a 20-fold selectivity over 5-LOX, 12-LOX, 15-LOX-1, COX-1, and COX-2. MLS000536924 is a competitive inhibitor with a Ki of 2.5+/-0.5 µM and also possesses 20-fold selectivity toward 15-LOX-2 over the other oxygenases, listed above. Finally, neither compound possesses reductive activity towards the active-site ferrous ion.

Show MeSH
Related in: MedlinePlus