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

Abstract

Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis (SSc); accounts for substantial morbidity and mortality; and lacks effective therapy. Recent findings implicated TGFβ-activated kinase 1 (TAK1), triggered by TGF-β and toll-like receptor signaling, in SSc pathogenesis. The objectives were to evaluate the activation of TAK1 signaling axis in SSc patients and to evaluate the antifibrotic ability of pharmacological TAK1 blockade in organ fibrosis. HS-276, a drug-like novel small molecule inhibitor of TAK1 was screened for its anti-fibrotic potential in cell cultures using foreskin, adult and SSc skin fibroblasts, and in bleomycin induced skin and lung fibrosis model.