Open AccessDiscovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents
Author(s) -
Shohei Miwa,
Masahiro Yokota,
Yuya Ueyama,
Kazuyuki Maeda,
Yosuke Ogoshi,
Noriyoshi Seki,
Naoki Ogawa,
Jun Nishihata,
Akihiro Nomura,
Tsutomu Adachi,
Yuki Kitao,
Keisuke Nozawa,
Tomohiro Ishikawa,
Yutaka Ukaji,
Makoto Shiozaki
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00679
Subject(s) - transforming growth factor , receptor , fibrosis , phenotype , rational design , signal transduction , growth factor , cancer research , transforming growth factor beta , pharmacology , microbiology and biotechnology , chemistry , medicine , biology , biochemistry , gene , genetics
Historically, modulation of transforming growth factor β (TGF-β) 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-β blockers, demonstrated significant therapeutic effects toward human skin fibrosis. Therefore, the selective blockage of TGF-β signaling assures a viable treatment option for fibrotic skin disorders such as systemic sclerosis (SSc). In this report, we disclose selective TGF-β type II receptor (TGF-βRII) 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-βRII-dependent signaling could be a new treatment for fibrotic disorders.