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Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds

Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Antifibrotic and Antimetastatic Compounds

Erika M Lisabeth, Dylan Kahl, Indiwari Gopallawa, Sarah E Haynes, Sean A Misek, Phillip L Campbell, Thomas S Dexheimer, Dinesh Khanna, David A Fox, Xiangshu Jin, Brent R Martin, Scott D Larsen, Richard R Neubig

ACS Pharmacol Transl Sci. 2019 Apr 12;2(2):92-100.

PMID: 32039344

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 co crystallizes with pirin, is also effective in the prevention of bleomycin-induced dermal fibrosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1443437748	CCG-203971		1443437-74-8	Price

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