Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents

Historically, modulation of transforming growth factor beta (TGF-beta) signaling has been deemed a rational strategy to treat many disorders, though few successful examples have been reported to date. This difficulty could be partially attributed to the challenges of achieving good specificity over many closely related enzymes that are implicated in distinct phenotypes in organ development and in tissue homeostasis. Recently, fresolimumab and disitertide, two peptidic TGF-beta blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefor; the selective blockage of TGF-beta signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-beta type II receptor (TGF-beta RII) inhibitors that exhibited high functional selectivity in cell-based assays. The representative compound 29 attenuated collagen type I alpha 1 chain (COL1A1) expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-beta RII-dependent signaling could be a new treatment for fibrotic disorders.

Automated summary

Selective blockage of TGF-beta signaling presents a promising treatment option for fibrotic skin disorders, as demonstrated by the therapeutic effects of fresolimumab and disitertide. The discovery of selective TGF-beta type II receptor inhibitors with high functional selectivity could offer a new treatment approach for fibrotic disorders.