ART26.12, an FABP5 Inhibitor, Shows Efficacy in Preclinical Psoriasis Models.

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, and markers of keratinocyte proliferation/differentiation and increased certain antimicrobial peptides. In vivo, ART26.12 (25 or 100 mg/kg twice a day) or BMS-986165 (TYK2 inhibitor; 10 mg/kg once a day) was given orally for 10 days in the imiquimod mouse model. Imiquimod increased psoriasis-like symptoms. ART26.12 (25 mg/kg twice a day) and BMS-986165 comparably reduced psoriasis-like symptoms by day 6 of imiquimod treatment. Histopathology showed that ART26.12 reduced symptom severity, for example, hyperkeratosis, parakeratosis, epidermal acanthosis, and inflammatory infiltrates. Proteomic analysis indicated that ART26.12 rescued the expression of FLG-2; promoted epidermal differentiation complex-associated proteins; and modulated peroxisome proliferator-activated receptor, NF-kB, and protein kinase C pathways likely downstream of lipid modulation. Lipidomic analysis showed widespread modulation, including ceramides and linoleic acid derivatives. These data suggest that ART26.12 may be a potential psoriasis treatment.