SIS3 hydrochloride is a specific inhibitor of Smad3 phosphorylation via inhibiting the effects of TGF-β1. Studies conducted on scleroderma fibroblasts indicate that SIS3 hydrochloride suppresses type I collagen up-regulation. In addition, SIS3 hydrochloride inhibits Smad-responsive p3TP promoter constructs activation. These studies suggest that SIS3 hydrochloride reduces DNA binding of Smad3 and that pretreatment with SIS3 hydrochloride decreases DNA binding by 50%. SIS3 hydrochloride also interferes with the interaction between contransfected Smad3 and Smad4. Furthermore, SIS3 hydrochloride reestablishes myofibroblast differentiation of scleroderma fibroblasts via reducing expression of α-SMA in these fibroblasts.
