Novel CYP26 inhibitors potentiate the effects of all-trans-retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis

Darier disease (DD) is a rare hereditary dominant human disorder characterized by warty papules and plaques in seborrheic areas of the skin. DD has a chronic course with frequent relapses while treatments often remain unsatisfactory. Retinoic Acid (RA) and its derivatives (retinoids) cause substantial clinical improvements in patients with DD. However, their use remains limited due to significant adverse effects. The endogenous concentration of RA is predominantly controlled via RA-inducible cytochrome P450 family 26 enzymes (CYP26), which inactivate RA by hydroxylation. As an alternative approach to therapeutic administration of retinoids, inhibition of CYP26 enzymes and thus of RA clearance represents an attractive strategy due to resulting elevated concentrations of endogenous RA. We previously designed and synthesized a CYP26A1/B1 dual inhibitor and inhibitors selective for either CYP26A1 or CYP26B1. In this study, we investigated the effects of RA alone or in combination with these CYP26 inhibitors on gene expression and on epidermal barrier using transepithelial electrical resistance (TEER), in reconstructed human epidermis (RHE) made of primary keratinocytes from either normal or DD patients. When the dual CYP26A1/B1 inhibitor was combined with RA (10-9 M), the TEER and the expression of differentiation markers were modulated similarly to the effects obtained with higher concentrations of RA. Our data revealed that dual selective inhibition of CYP26A1/B1 with our new compound DX308 potentiates the effect of RA at low concentration on RHE. Hence, the result of this study indicates that dual inhibition of CYP26A1 and B1 by DX308 may represent a promising therapeutic strategy for the treatment of DD with reduced retinoid-induced adverse effects.