7DV6

Discovery of Functionally Selective Transforming Growth Factor beta Type II Receptor (TGF-beta RII) Inhibitors as Anti-Fibrosis Agents

7DV6 の概要

• エントリーDOI: 10.2210/pdb7dv6/pdb
• 分子名称: TGF-beta receptor type-2, 5-[(3S)-5,5-dimethyloxolan-3-yl]-6-methoxy-3-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine (3 entities in total)
• 機能のキーワード: inhibitor, complex, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37142.11

構造登録者

Nishihata, J.,Nomura, A.,Miwa, S.,Doi, S.,Adachi, T. (登録日: 2021-01-12, 公開日: 2021-06-16, 最終更新日: 2023-11-29)

主引用文献

Miwa, S.,Yokota, M.,Ueyama, Y.,Maeda, K.,Ogoshi, Y.,Seki, N.,Ogawa, N.,Nishihata, J.,Nomura, A.,Adachi, T.,Kitao, Y.,Nozawa, K.,Ishikawa, T.,Ukaji, Y.,Shiozaki, M.
Discovery of Selective Transforming Growth Factor beta Type II Receptor Inhibitors as Antifibrosis Agents.
Acs Med.Chem.Lett., 12:745-751, 2021

PubMed Abstract: 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 attenuated collagen type I alpha 1 chain () expression in a mouse fibrosis model, which suggests that selective inhibition of TGF-βRII-dependent signaling could be a new treatment for fibrotic disorders.

PubMed: 34055221
DOI: 10.1021/acsmedchemlett.0c00679

実験手法

X-RAY DIFFRACTION (2.39 Å)