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
  • 1. UCL Institute of Ophthalmology, London, UK. [email protected].
  • 2. National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK. [email protected].
  • 3. Signalling and Transcription Group, Francis Crick Institute, London, UK. [email protected].
  • 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.

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