5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic Acids: A Highly Potent New Class of Inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-Mediated Gene Transcription as Potential Antifibrotic Agents for Scleroderma

Abstract

Through a phenotypic high throughput screen (HTS) using a serum response element luciferase (SRE.L) promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/MRTF/SRF-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 μM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor (CTGF) gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.

Crystalline Silica Impairs Efferocytosis Abilities of Human and Mouse Macrophages: Implication for Silica-Associated Systemic Sclerosis

“…New Rho inhibitors have been recently design for the treatment of SSc with promising results on dermal fibrosis in the bleomycin SSc mouse model (23). Beyond fibroblasts, the authors announce that identifying other biological targets of these new Rho inhibitors is a new key step for scleroderma research (23). Our results suggest that M could constitute such relevant targets.…”

“…Interestingly, significant associations between ROCK1/2 and RhoA gene polymorphisms and SSc have been reported, which also strengthens the possible role of this pathway in this systemic autoimmune disorder (52). New Rho inhibitors have been recently design for the treatment of SSc with promising results on dermal fibrosis in the bleomycin SSc mouse model (23). Beyond fibroblasts, the authors announce that identifying other biological targets of these new Rho inhibitors is a new key step for scleroderma research (23).…”

“…In the present study, we first aim to determine whether SiO 2 might alter efferocytosis capacities of human and mouse M . We secondly explore possible mechanisms that could explain an impaired efferocytosis, with a specific focus on M polarization and on the RhoA/ROCK pathway, a key regulator of cell adhesion, cytoskeleton remodeling and phagocytosis, that has been recently advanced as a promising therapeutic target in fibrotic disease and especially in SSc (23,24).…”

Bad Neighborhood: Fibrotic Stroma as a New Player in Melanoma Resistance to Targeted Therapies

“…Another critical regulator that links mechanical cues to aberrant remodeling of the extracellular matrix in fibrosis is MRTF. Anti-fibrotic agents inhibiting Rho/MRTF/SRF-mediated gene transcription significantly impair the development of bleomycin-induced dermal fibrosis in vivo [136] and decrease the activation of pancreatic stellate cells in the tumor microenvironment, ameliorating the possibilities of therapeutic intervention [137]. Rho/MRTF signaling is not only involved in the fibrogenic process but also in the aggressive phenotype of metastatic melanoma.…”

Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma

“…Bleomycin-induced skin fibrosis. The procedure to induce fibrosis by bleomycin in mice was published previously (2,13). Bleomycin was dissolved to 1 mg/ml with PBS.…”