Fiboflapon Sodium

Human B-lymphocytes express 5-lipoxygenase (5-LOX) and 5-LOX activating protein (FLAP) and can convert arachidonic acid to leukotriene B₄. Mantle cell lymphoma (MCL) cells contain similar amounts of 5-LOX as human neutrophils but the function and mechanism of activation of 5-LOX in MCL cells, and in normal B-lymphocytes, are unclear. Here we show that the intrinsic 5-LOX pathway in the MCL cell line JeKo-1 has an essential role in migration and adherence of the cells, which are important pathophysiological characteristics of B-cell lymphoma. Incubation of JeKo-1 with the FLAP inhibitor GSK2190915 or the 5-LOX inhibitor zileuton, at a concentration below 1 μM, prior to stimulation with the chemotactic agent CXCL12, led to a significant reduction of migration. CRISPR/Cas9 mediated deletion of ALOX5 gene in JeKo-1 cells also led to a significantly decreased migration of the cells. Furthermore, 5-LOX and FLAP inhibitors markedly decreased the adherence of JeKo-1 cells to stromal cells. In comparison, these drugs had a similar effect on adherence of JeKo-1 cells as the Bruton tyrosine kinase inhibitor ibrutinib, which has a proven anti-tumour effect. These results indicate that inhibition of 5-LOX may be a novel treatment for MCL and certain other B-cell lymphomas.

Inflammatory diseases can be treated by inhibiting 5‐lipo‐oxygenase activating protein (FLAP). In this study, a data set containing 2,112 FLAP inhibitors was collected. A total of 25 classification models were built by five machine learning algorithms with five different types of fingerprints. The best model, which was built by support vector machine algorithm with ECFP_4 fingerprint had an accuracy and a Matthews correlation coefficient of 0.862 and 0.722 on the test set, respectively. The predicted results were further evaluated by the application domain dSTD‐PRO (a distance between one compound to models). Each compound had a dSTD‐PRO value, which was calculated by the predicted probabilities obtained from all 25 models. The application domain results suggested that the reliability of predicted results depended mainly on the compounds themselves rather than algorithms or fingerprints. A group of customized 10‐bit fingerprint was manually defined for clustering the molecular structures of 2,112 FLAP inhibitors into eight subsets by K‐Means. According to the clustering results, most of inhibitors in two subsets (subsets 2 and 4) were highly active inhibitors. We found that aryl oxadiazole/oxazole alkanes, biaryl amino‐heteroarenes, two aromatic rings (often N‐containing) linked by a cyclobutene group, and 1,2,4‐triazole group were typical fragments in highly active inhibitors.