title: Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis.
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 IC50of 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.
authors.affiliation: UCL Institute of Ophthalmology, London, UK. c.yu-wai-man@ucl.ac.uk.|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.|Signalling and Transcription Group, Francis Crick Institute, London, UK. c.yu-wai-man@ucl.ac.uk.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Yu-Wai-Man
authors.affiliation: Experimental Histopathology STP, Francis Crick Institute, London, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Richard M H
authors.initials: RMH
authors.lastname: Lee
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Hutchings
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Lisabeth
authors.affiliation: Signalling and Transcription Group, Francis Crick Institute, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Treisman
authors.affiliation: UCL Institute of Ophthalmology, London, UK.
authors.forename: Maryse
authors.identifier: http://orcid.org/0000-0002-0593-6356
authors.initials: M
authors.lastname: Bailly
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.affiliation: National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.
authors.forename: Peng T
authors.initials: PT
authors.lastname: Khaw
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005109:Extracellular Matrix; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D011817:Rabbits; D026362:Serum Response Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D026362:Serum Response Factor; D015534:Trans-Activators; D003094:Collagen