Mitogen-activated protein kinase p38 is a stress-induced intracellular kinase that plays essential roles in the regulation of cellular responses, including migration, cytokine expression, and contraction. Losmapimod is a potent, orally active inhibitor of p38α and p38β with pKi values of 8.1 and 7.6, respectively[1]. In gefitinib-resistant cells (HCC827GR and H1975), treatment of 1 μM losmapimod for 10 hours inhibited gefitinib-induced phosphorylation of STAT3 and expressions of p21 and cyclin D1. Combined treatment of gefitinib (1 μM) and losmapimod (1 μM) significantly suppressed anchorage-independent cell growth and proliferation in NSCLC cells[2]. Spontaneously hypertensive stroke-prone rat (SHR-SP) placed on high salt-fat diet (SFD) for 8 weeks showed 50% survival rate and increased mean blood pressure. Dietary administration of losmapimod (1.2 and 12 mg/kg/day doses) significantly elevated the survival rate. Animals receiving 12 mg/kg/day losmapimod also showed suppressed mean blood pressure compared to untreated SFD-fed rats. Treatment of losmapimod (1.2 and 12 mg/kg/day doses) for 6 weeks attenuated SFD-induced increase in urine flow, FENa, albumin excretion, creatinine clearance, and kidney weight. Rats administered with 12 mg/kg/day losmapimod showed reduced left ventricular mass and wall thickness compared with untreated SFD-fed rats. Endothelial-dependent and endothelium-independent vasorelaxation were also improved by losmapimod treatment at a dose-dependent manner[1].
作用机制
Losmapimod selectively and potently inhibits p38 via competing for the kinase ATP binding site[1].
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