Oct 31, 2018

Identification of Pirin as a Molecular Target of the CCG-1423/CCG-203971 Series of Anti-Fibrotic and Anti-Metastatic Compounds

BioRxiv : the Preprint Server for Biology
Erika M LisabethRichard R Neubig

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 melanoma metastasis and bleomycin-induced fibrosis. Although these compounds are efficacious, the molecular target is unknown. Here, we describe affinity isolation-based target identification efforts which yielded pirin, an iron-dependent co-transcription 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 SRE.L Luciferase activation. 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.

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Mentioned in this Paper

root-associated fungal sp. SRE-2008-1
In Vivo
Specimen Type - Fibroblasts
L-CCG-II
RNA, Small Interfering
Isolation Aspects
Inhibitors
CCG 1423
MKL/Myocardin-Like Protein 1
Crystallography, X-Ray

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