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Novel Rho/MRTF/SRF Inhibitors Block Matrix-Stiffness and TGF-β-induced Fibrogenesis in Human Colonic Myofibroblasts

Novel Rho/MRTF/SRF Inhibitors Block Matrix-Stiffness and TGF-β-induced Fibrogenesis in Human Colonic Myofibroblasts

Laura A Johnson, Eva S Rodansky, Andrew J Haak, Scott D Larsen, Richard R Neubig, Peter D R Higgins

Inflamm Bowel Dis. 2014 Jan;20(1):154-65.

PMID: 24280883

Abstract:

Background:
Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil forming protein kinase signaling is a key pathway in multiple types of solid organ fibrosis, including intestinal fibrosis. However, the pleiotropic effects of RhoA/Rho-associated coiled-coil forming protein kinase signaling have frustrated targeted drug discovery efforts. Recent recognition of the role of Rho-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) suggest a novel locus for pharmacological intervention.
Methods:
Because RhoA signaling is mediated by both physical and biochemical stimuli, we examined whether pharmacological inhibition of RhoA or the downstream transcription pathway of MRTF-A/SRF could block intestinal fibrogenesis in 2 in vitro models.
Results:
In this study, we demonstrate that inhibition of RhoA signaling blocks both matrix-stiffness and transforming growth factor beta-induced fibrogenesis in human colonic myofibroblasts. Repression of alpha-smooth muscle actin and collagen expression was associated with the inhibition of MRTF-A nuclear localization. CCG-1423, a first-generation Rho/MRTF/SRF pathway inhibitor, repressed fibrogenesis in both models, yet has unacceptable cytotoxicity. Novel second-generation inhibitors (CCG-100602 and CCG-203971) repressed both matrix-stiffness and transforming growth factor beta-mediated fibrogenesis as determined by protein and gene expression in a dose-dependent manner.
Conclusions:
Targeting the Rho/MRTF/SRF mechanism with second-generation Rho/MRTF/SRF inhibitors may represent a novel approach to antifibrotic therapeutics.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1207113889	CCG-100602		1207113-88-9	Price

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