Characterization of CYP26B1-selective inhibitor, DX314, as a potential therapeutic for keratinization disorders

Joachim Veit, VALERIE DE GLAS, Benoit Balau, Haoming Liu, Florence Bourlond, Amy Paller, Yves POUMAY, Philippe Diaz

Research output: Contribution to journalArticle

Abstract

Inhibition of cytochrome P450 (CYP)-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents (RAMBAs) increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RAMBAs (i.e. liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study we use RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA (atRA) in healthy and diseased reconstructed human epidermis (RHE). We unexpectedly discovered that DX314, but not atRA or previous RAMBAs, appears to protect epidermal barrier integrity. Additionally, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, results indicate that DX314 inhibits atRA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a previously unreported promising candidate compound for further study and development in the context of keratinization disorders.
Original languageEnglish
JournalThe journal of investigative dermatology
Early online date3 Jun 2020
DOIs
Publication statusPublished - 3 Jun 2020

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