7DV6

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

Summary for 7DV6

• Entry DOI: 10.2210/pdb7dv6/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37142.11

Authors

Nishihata, J.,Nomura, A.,Miwa, S.,Doi, S.,Adachi, T. (deposition date: 2021-01-12, release date: 2021-06-16, Last modification date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.39 Å)