Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds
Year: 2019
Type: article
Abstract: A series of compounds (including CCG-1423 and CCG-203971) discovered through an MRTF/SRF-dependent luciferase screen has shown remarkable efficacy in a variety of in vitro and in vivo models, including significant reduction of melanoma metastasis and bleomycin-induced fibrosis. Although these compounds are efficacious in these disease models, the molecular target is unknown. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent cotranscription factor, as a target of this series of compounds. Using biophysical techniques including isothermal titration calorimetry and X-ray crystallography, we verify that pirin binds these compounds in vitro . We also show with genetic approaches that pirin modulates MRTF-dependent luciferase reporter activity. Finally, using both siRNA and a previously validated pirin inhibitor, we show a role for pirin in TGF-β-induced gene expression in primary dermal fibroblasts. A recently developed analog, CCG-257081, which cocrystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis.
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Energy, Michigan Economic Development Corporation, National Institutes of Health, Office of Science, University of California, San Francisco, Michigan Technology Tri-Corridor, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Argonne National Laboratory
Awards: G102163711, G107546177, G1136886101, G1313983767, G1505794299, G1664757510, G1907146399, G1947107004, G2101401529, G2287611682, G2572128430, G262962599, Inhibition of the Rho/MRTF/SRF Pathway as a New Treatment for Systemic Sclerosis, G2887060908, G2896567508, G3075337988, G3329398301, G340396948, G340565428, G409777406, G416541740, G4773269573, G4815039349, G498139845, G5106849484, G5190802742, G5607048534, G5906309288, G6101244626, G6285642246, G6848031779, G6918803902, G6967276973, G7147508703, G7368700025, G8764064047, G9000001160, G9000094659, G9000131913, G969889393, G993149817
OpenAlex ID: W4248747409