599 Selective inhibition Of fibro-inflammatory kinase TAK1: A potential therapeutic strategy to ameliorate systemic sclerosis

Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis (SSc); accounts for substantial morbidity mortality; lacks effective therapy. Recent findings implicated TGFβ-activated kinase 1 (TAK1), triggered by TGF-β toll-like receptor signaling, SSc pathogenesis. The objectives were evaluate activation TAK1 signaling axis patients antifibrotic ability pharmacological blockade organ fibrosis. HS-276, a drug-like novel small molecule inhibitor was screened its anti-fibrotic potential cell cultures using foreskin, adult skin fibroblasts, bleomycin induced lung fibrosis model. HS-276 treatment ameliorated dermal pulmonary reduced expression several pro-fibrotic mediators bleomycin-treated mice compared vehicle-treated control. Importantly, regression pre-established abrogated TGF-β1-induced collagen synthesis myofibroblasts differentiation explanted normal fibroblasts (neonatal adult) constitutively active fibroblasts. effects accompanied phosphorylation p38 MAPK JNK as well IL-6 inflammatory markers. These implicate significance pathway identify agent fibrotic diseases.