2. Academic Validation
  3. Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

  • Sci Rep. 2017 Mar 31;7(1):518. doi: 10.1038/s41598-017-00212-w.
Cynthia Yu-Wai-Man 1 2 3,  Bradley Spencer-Dene 4,  Richard M H Lee 5,  Kim Hutchings 6,  Erika M Lisabeth 7,  Richard Treisman 8,  Maryse Bailly 9,  Scott D Larsen 6,  Richard R Neubig 7,  Peng T Khaw 5
Affiliations

Affiliations

  • 1 UCL Institute of Ophthalmology, London, UK. c.yu-wai-man@ucl.ac.uk.
  • 2 National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. c.yu-wai-man@ucl.ac.uk.
  • 3 Signalling and Transcription Group, Francis Crick Institute, London, UK. c.yu-wai-man@ucl.ac.uk.
  • 4 Experimental Histopathology STP, Francis Crick Institute, London, UK.
  • 5 National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
  • 6 Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
  • 7 Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
  • 8 Signalling and Transcription Group, Francis Crick Institute, London, UK.
  • 9 UCL Institute of Ophthalmology, London, UK.
PMID: 28364121 DOI: 10.1038/s41598-017-00212-w
Abstract

The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and Other tissues.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-121750
    99.85%, Rho/MRTF/SRF 抑制剂
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