Prediction and Demonstration of Retinoic Acid Receptor Agonist Ch55 as an Antifibrotic Agent in the Dermis

The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel antifibrotic therapies. The repurposing of drugs with existing mechanisms of action and/or clinical data is a promising approach for the treatment of fibrotic diseases. One paradigm that pervades all fibrotic diseases is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for the deposition of fibrotic tissue. In this study, we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and thus contain the potential for use as antifibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to fibroblasts, and identified the retinoic acid receptor agonist Ch55 as a potential hit. Further investigation exhibited and elucidated the antifibrotic effects of Ch55 in vitro as well as showing antiscarring activity upon intradermal application in a preclinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover antiscarring compounds may yield further preclinical and ultimately clinical success.

Automated summary

The discovery of novel antifibrotic therapies is of great importance due to the high prevalence of fibrotic diseases and the lack of effective pharmacologic modalities. Repurposing drugs with existing mechanisms of action and/or clinical data is a promising approach for treating fibrotic diseases. This study used a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map to select compounds that have the potential to reverse the pathological gene expression signature associated with myofibroblasts and act as antifibrotic compounds. Testing on fibroblasts identified the retinoic acid receptor agonist Ch55 as a potential hit, and further investigation demonstrated its antifibrotic effects and antiscarring activity in vitro and in a preclinical rabbit ear hypertrophic scar model. The discovery of antiscarring compounds through similar predictions may lead to further preclinical and ultimately clinical success.