4 years ago

ITK and RLK inhibitor PRN694 improves skin disease in two mouse models of psoriasis.

Jens Oliver Funk, Mårten C G Winge, Jessica M Fuhriman, M Peter Marinkovich, J Michael Bradshaw, Helena Haberstock-Debic
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 pro-inflammatory 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 upregulated in psoriatic skin. These TEC kinases are involved in signaling cascades mediating T lymphocyte proliferation, differentiation, migration, and proinflammatory cytokine production. In vitro analysis showed that PRN694 effectively inhibited IL-17A production from murine TH17 differentiated T lymphocytes. Additionally, PRN694 effectively reduced the psoriasis-like phenotype severity and reduced epidermal proliferation and thickness in both the Rac1(V12) and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3+ T cell and γ/δT cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, implicating PRN694 is an effective psoriasis therapeutic.

Publisher URL: http://doi.org/10.1016/j.jid.2017.10.029

DOI: 10.1016/j.jid.2017.10.029

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