610 Identification of the selective glucocorticoid receptor agonist Mapracorat as potential new drug for chronic wound therapy

Abstract

We have shown that the effects of wound exudates on fibroblast cultures reflect their clinical healing phenotype and can thus serve as a functional biomarker. We used this assay for screening to identify compounds or compound classes with so far unknown potential for chronic wound therapy. The selective glucocorticoid receptor agonist (SEGRA) Mapracorat was found to reverse the inhibitory effect of several exudates. The compound was profiled in additional exudate-based cellular assays to investigate its suitability for wound therapy. Primary human dermal fibroblasts were grown in 384-well plates in 2D and 3D cultures. Mapracorat was added to the cells in the presence of wound exudates from different chronic wound patients. Incubation times were 72 hours for 2D cultures and 4 – 8 days for 3D cultures. Supernatants were then harvested for the determination of IL-1beta, RNA was extracted for RT-PCR, or cells were fixed and stained for cellular protein. Mapracorat rescued inhibition of wound exudate-induced fibroblast proliferation in 80% of 200 exudates tested. For 95/200 exudates from chronic wounds of different etiologies, cell proliferation was increased by Mapracorat by >150% compared to exudate alone, and complete recovery was demonstrated in 25% of these samples. This rescue effect was achieved at low nanomolar concentrations. The compound dose-dependently inhibited IL-1beta production and enhanced matrix formation as well as collagen 1 and collagen 3 mRNA expression, indicating transition from a chronic/non-healing to a healing phenotype ex vivo. In functional ex vivo assays for chronic wounds, Mapracorat reversed the detrimental effects of wound exudates on fibroblast proliferation and matrix formation, and reduced proinflammatory cytokine secretion. Mapracorat showed good or excellent activity with almost 50% of exudates. To select the patients best suited for therapy with this compound, theranostic pretesting is recommended.