Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes
Open Access
- 27 June 2016
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 358 (3), 413-422
- https://doi.org/10.1124/jpet.116.232819
Abstract
Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole PDE4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole (AN2728), compd2, compd3, and compd4 are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bi-metal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of TNF-α, IL-23, IL-17, IFN-γ, IL-4, IL-5, IL-13 and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or dBcAMP increases CREB phosphorylation in human monocytes and decreases ERK phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses PMA-induced IL-13, IL-22, IL-17F and IL-23 transcription and calcipotriol-induced TSLP expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. In contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.Keywords
This publication has 68 references indexed in Scilit:
- The role of IL-22 and Th22 cells in human skin diseasesJournal of Dermatological Science, 2013
- Phosphodiesterase 4-targeted treatments for autoimmune diseasesBMC Medicine, 2013
- Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitisJournal of Allergy and Clinical Immunology, 2012
- Contrasting pathogenesis of atopic dermatitis and psoriasis—Part II: Immune cell subsets and therapeutic conceptsJournal of Allergy and Clinical Immunology, 2011
- Contrasting pathogenesis of atopic dermatitis and psoriasis—Part I: Clinical and pathologic conceptsJournal of Allergy and Clinical Immunology, 2011
- The Role of the Transcription Factor CREB in Immune FunctionThe Journal of Immunology, 2010
- Cross Talk between Phosphatidylinositol 3-Kinase and Cyclic AMP (cAMP)-Protein Kinase A Signaling Pathways at the Level of a Protein Kinase B/β-Arrestin/cAMP Phosphodiesterase 4 ComplexMolecular and Cellular Biology, 2010
- Sensing the outside world: TSLP regulates barrier immunityNature Immunology, 2010
- IL-22–producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17–producing TH17 T cellsJournal of Allergy and Clinical Immunology, 2009
- Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitisProceedings of the National Academy of Sciences of the United States of America, 2006