310 PI3-Kinase inhibitors represent a novel class of drug repurposing candidates to prevent glucocorticoid-induced skin atrophy

Abstract

Skin atrophy is a major adverse effect of topical glucocorticoids (Gcs). We recently reported that REDD1 (regulated in development and DNA damage 1) and FKBP51 (FK506 binding protein 5), negative regulators of mTOR/Akt signaling, induced by Gcs in mouse and human skin, act as central drivers of steroid skin atrophy. Thus, we assumed that REDD1/FKBP51 inhibitors could protect skin against catabolic effects of glucocorticoids. Using drug repurposing approach, we screened LINCS library (http://lincsproject.org/LINCS/) to identify repressors of REDD1 and FKBP51 expression. Bioinformatics analysis unexpectedly identified phosphoinositide-3-kinase (PI3K)/mTOR/Akt inhibitors as a pharmacological class of REDD1/FKBP51 repressors. Seven selected PI3K/mTOR/Akt inhibitors: Rapamycin*, OSI-027*, Wortmannin (WM), LY294002, AZD8055*, NVP-BEZ235*, MK-2206* (star indicates drugs in clinic/clinical trials) indeed blocked basal and Gcs-induced REDD1/FKBP51 expression in human primary/immortalized keratinocytes and in mouse skin. Most of PI3K/mTOR/Akt inhibitors also modified global effect of Gcs on trascriptome, shifting it towards therapeutically important transrepression; negatively impacted the glucocorticoid receptor (GR) phosphorylation; nuclear translocation; and GR loading on gene promoters. Most importantly, topical application of Rapamycin and LY294002 together with fluocinolone acetonide (FA) protected mice against FA-induced proliferative block and epidermal, dermal and dWAT atrophy but did not alter FA anti-inflammatory activity in ear edema test. LY294002 also partially protected skin from Dexamethason-induced skin hypoplasia when both were delivered systemically via i.p. injections. Our results built a strong foundation for development of safer GR-targeted therapies for inflammatory skin diseases using combination of glucocorticoids with PI3K/mTOR/Akt inhibitors.