Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents
| Autor: | Yoshifumi Ueyama, Yutaka Ukaji, Keisuke Nozawa, Katsuya Maeda, Shohei Miwa, Tomohiro Ishikawa, Yuki Kitao, Tsuyoshi Adachi, Naoki Ogawa, Makoto Shiozaki, Yokota Masahiro, Yosuke Ogoshi, Seki Noriyoshi, Jun Nishihata, Akihiro Nomura |
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| Rok vydání: | 2020 |
| Předmět: |
010405 organic chemistry
Chemistry Organic Chemistry Human skin medicine.disease 01 natural sciences Biochemistry Phenotype 0104 chemical sciences 010404 medicinal & biomolecular chemistry Collagen type I alpha 1 Fibrosis Drug Discovery Cancer research Functional selectivity medicine Receptor Tissue homeostasis Transforming growth factor |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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