ART26.12, A FATTY ACID-BINDING PROTEIN 5 INHIBITOR, SHOWS EFFICACY IN PRECLINICAL PSORIASIS MODELS

Fatty acid-binding protein 5 (FABP5) is upregulated in psoriasis. This study assessed the efficacy of the potent, selective, and orally active FABP5 inhibitor ART26.12 in preclinical psoriasis models. In vitro, reconstructed human epidermis was stimulated with cytokines (IL-17 + IL-22 + TNF at 3 ng/ml each) and treated with ART26.12 (1, 3, or 10 μM) or JAK1 inhibitor (10 μM) for 24 hours, after which, 64 psoriasis-related genes were measured. ART26.12 (3 and 10 μM) treatment reduced cytokines, chemokines, markers of keratinocyte proliferation/differentiation, and increased certain antimicrobial peptides. In vivo, ART26.12 (25 or 100 mg/kg BID) or BMS-986165 (TYK2 inhibitor; 10 mg/kg QD) were given orally for 10 days in the imiquimod mouse model. Imiquimod increased psoriasis-like symptoms. ART26.12 (25 mg/kg BID) and BMS-986165 comparably reduced psoriasis-like symptoms by Day 6 of IMQ treatment. Histopathology showed that ART26.12 reduced symptom severity, e.g., hyperkeratosis, parakeratosis, epidermal acanthosis, and inflammatory infiltrates. Proteomic analysis indicated ART26.12 rescued expression of fillagrin-2, promoted epidermal differentiation complex associated proteins and modulated PPAR, NF-kB, and PKC pathways likely downstream of lipid modulation. Lipidomic analysis showed widespread modulation including ceramides and linoleic acid derivatives. These data suggest ART26.12 may be a potential psoriasis treatment.