prn694 and Psoriasis

Psoriasis is a common inflammatory condition found in 1-2% of the population. The greatest advances in psoriasis treatment have occurred in patients with severe psoriasis, moving from systemic small molecules including methotrexate, cyclosporine, and retinoids to targeted agents against psoriasis-associated cytokines, such as TNF-α, IL-12, IL-23, and IL-17. Although the new biologics do not have the same adverse effects as the systemic drugs, they do predispose to systemic infections (and perhaps cancer), and they are extremely expensive. The focus on biologic therapies has been accompanied by a relative neglect of small molecules, which can be used either topically or systemically. No small molecule has been able to compete significantly with topical glucocorticoids, the mainstay of treatment for mild to moderate psoriasis for more than half a century.

Topics: Animals; Benzimidazoles; Dermatologic Agents; Humans; Methotrexate; Mice; Psoriasis

The chronic and highly prevalent skin disorder psoriasis vulgaris is characterized by a hyperproliferative epidermis and aberrant immune activity. Many studies have highlighted the role of differentiated T lymphocytes in psoriasis progression. Several biologics are currently available that target proinflammatory cytokines produced by T lymphocytes, but the need for improved therapies persists. The small molecule PRN694 covalently binds ITK and RLK, two Tec kinases activated downstream of T-lymphocyte activation, both of which are up-regulated in psoriatic skin. These Tec kinases are involved in signaling cascades mediating T-lymphocyte proliferation, differentiation, and migration and proinflammatory cytokine production. In vitro analysis showed that PRN694 effectively inhibited IL-17A production from murine T helper type 17-differentiated T lymphocytes. Additionally, PRN694 effectively reduced the psoriasis-like phenotype severity and reduced epidermal proliferation and thickness in both the Rac1

Topics: Animals; Benzimidazoles; Cells, Cultured; Dermis; Disease Models, Animal; Gene Expression Regulation; Humans; Immunity, Cellular; Mice; Protein-Tyrosine Kinases; Psoriasis; RNA, Messenger; T-Lymphocytes