Novel p38 MAPK inhibitor ML3403 has potent anti-inflammatory activity in airway smooth muscle
Novel p38 MAPK inhibitor ML3403 has potent anti-inflammatory activity in airway smooth muscle
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DOI：
10.1016/j.ejphar.2010.02.037
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发表时间：
2010-06-10
影响因子：
5
通讯作者：
Ammit, Alaina J.
中科院分区：
文献类型：
--
作者：
Munoz, Lenka;Ramsay, Emma E.;Ammit, Alaina J.
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SB203580 is the prototypical p38 MAPK inhibitor; however it cannot be used clinically due to liver toxicity. We developed a structural analogue of SB203580 - ML3403 - with equal in vitro and ex vivo p38 alpha MAPK inhibition as SB203580, but with reduced activity towards liver cytochrome P450 enzymes. In addition, we developed a selective p38 alpha MAPK inhibitor CP41. The aim of this study is to compare the anti-inflammatory activity of MI3403 and CP41, with SB203580. We compare and contrast the ability of the p38 MAPK inhibitors to repress tumour necrosis factor alpha (TNF alpha)-induced interleukin 6 (IL-6) and interleukin 8 (IL-8) mRNA expression and protein secretion from airway smooth muscle cells. We also examined and compared the binding affinities of ML3403 and SB203580 to the active and inactive p38 alpha MAPK. We demonstrate that ML3403 binds to both active and inactive p38 MAPK with high affinity and that it inhibits p38 MAPK-mediated airway smooth muscle synthetic function to an equivalent degree with SB203580. CP41 was not able to reduce IL-6 and IL-8 secretion in airway smooth muscle cells; a function of its higher IC50 against p38 alpha MAPK when compared to SB203580 and ML3403. We show that p38 MAPK-mediated pro-inflammatory pathways in airway smooth muscle cells can be inhibited by ML3403. The anti-inflammatory activity is equivalent to the prototypical p38 MAPK inhibitor SB203580. Our results implicate a future pharmacotherapeutic strategy towards reducing inflammation in asthma and airway remodelling. (C) 2010 Elsevier B.V. All rights reserved.