Prolyl-tRNA synthetase inhibitor as a novel first-in-class keloid treatment: downregulation of de novo collagen synthesis and inflammatory cascade

BACKGROUND: Keloids are severe dermal fibrotic disorders caused by excessive deposition of collagen. Current therapies have high recurrence rates, and there is a clinical need for a new, fundamental approach. We focused on inhibiting proline, an essential amino acid for collagen biosynthesis. We developed DWN12088, a drug that downregulates prolyl-tRNA synthetase (PRS), an enzyme involved in proline ligation. OBJECTIVES: To investigate the antifibrotic activity of selective PRS inhibitors and elucidate the importance of DWN12088 as a first-in-class therapeutic agent for keloids. METHODS: Patient-derived keloid fibroblasts (KFs) and keloid tissues were obtained to observe PRS upregulation. In addition, the antifibrotic activity of selective PRS inhibitors was studied using KFs, and their treatment efficacy further validated in vivo using a KF xenograft severe combined immunodeficient (SCID) mouse model. Histological and immunohistochemistry analyses were performed with human-derived keloid tissues. Additional experiments included immunocytochemistry, cell viability analysis, migration analysis and Western blotting of KFs. Human KFs were injected into SCID mice to study nodule formation and histological characteristics. RESULTS: Compared with normal fibroblasts and healthy skin tissues, PRS was overexpressed in KFs and keloid tissues. A selective PRS inhibitor downregulated fibrotic markers, reduced migration capacity and lowered collagen production in KFs. In a KF xenograft SCID mouse model, a selective PRS inhibitor effectively suppressed keloid formation and mitigated inflammation and fibrosis. CONCLUSIONS: DWN12088, a selective PRS inhibitor, may be a novel first-in-class treatment modality that effectively prevents keloid development. Further clinical trials are required to verify the safety and clinical efficacy of PRS inhibitors for keloids. We believe that our study has applicability across several fibrotic wound problems such as hypertrophic scars.