Song Jiao, Liu Xuejun, Zhu Jian, Tootoonchi Mandana, Keith John M, Meduna Steven P, Dvorak Curt A, Eccles Wendy, Krawczuk Paul J, Blevitt Jonathan M, Wu Jiejun, Rao Navin L, Lebsack Alec D, Milla Marcos E
Discovery Sciences, Janssen Research & Development, LLC, La Jolla, CA, USA.
Immunology, Janssen Research & Development, LLC, La Jolla, CA, USA.
J Biomol Screen. 2016 Feb;21(2):127-35. doi: 10.1177/1087057115607815. Epub 2015 Oct 6.
Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.
白三烯（LTs）及相关物质是源自花生四烯酸（AA）的促炎脂质介质，在自身免疫和炎症性疾病、心血管疾病及癌症中发挥病理作用。5-脂氧合酶激活蛋白（FLAP）在AA转化为白三烯A4（LTA4）以及随后LTA4由白三烯C4合成酶转化为白三烯C4（LTC4）的过程中起关键辅助作用。对FLAP的药理抑制可通过阻止白三烯B4（LTB4）和LTC4的生物合成导致LT生成减少，这使其成为治疗可能由LTs发挥作用的炎症性疾病的一个有吸引力的靶点。小分子（SM）药物通常通过各种途径表现出多药理学特性，这可能解释了具有结构相似性的化合物的不同治疗效果。我们使用最近开发的基于液相色谱-质谱联用（LC/MS）的高通量脂质组学平台，该平台可多路监测122种类二十烷酸，对一系列SM FLAP调节剂在人全血（HWB）中AA级联反应的各种酶上的选择性进行了分析。高效的数据采集与快速准确的数据分析相结合，使得能够从离体研究样本中轻松地对化合物进行分析。该平台使我们能够定量绘制这些SMs对整个AA级联反应的影响，证明了其区分结构相关化合物的潜力。
