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SIS3 is a potent and selective inhibitor of Smad3 and TGF-β signaling. Inhibition by SIS3 leads to abrogation of the TGF-β1-induced production of extracellular matrix proteins in normal fibroblasts and scleroderma fibroblasts. Moreover, Smad3 inhibition attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells.