- Kenyon, Victor;
- Rai, Ganesha;
- Jadhav, Ajit;
- Schultz, Lena;
- Armstrong, Michelle;
- Jameson, J Brian;
- Perry, Steven;
- Joshi, Netra;
- Bougie, James M;
- Leister, William;
- Taylor-Fishwick, David A;
- Nadler, Jerry L;
- Holinstat, Michael;
- Simeonov, Anton;
- Maloney, David J;
- Holman, Theodore R
We report the discovery of novel small molecule inhibitors of platelet-type 12-human lipoxygenase, which display nanomolar activity against the purified enzyme, using a quantitative high-throughput screen (qHTS) on a library of 153607 compounds. These compounds also exhibit excellent specificity, >50-fold selectivity vs the paralogues, 5-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity vs ovine cyclooxygenase-1 and human cyclooxygenase-2. Kinetic experiments indicate this chemotype is a noncompetitive inhibitor that does not reduce the active site iron. Moreover, chiral HPLC separation of two of the racemic lead molecules revealed a strong preference for the (-)-enantiomers (IC(50) of 0.43 ± 0.04 and 0.38 ± 0.05 μM) compared to the (+)-enantiomers (IC(50) of >25 μM for both), indicating a fine degree of selectivity in the active site due to chiral geometry. In addition, these compounds demonstrate efficacy in cellular models, which underscores their relevance to disease modification.