Skip to main content
 
Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
Stanford Health Care

ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis.

ITK and RLK Inhibitor PRN694 Improves Skin Disease in Two Mouse Models of Psoriasis. The Journal of investigative dermatology Fuhriman, J. M., Winge, M. C., Haberstock-Debic, H., Funk, J. O., Bradshaw, J. M., Marinkovich, M. P. 2018; 138 (4): 864–71

Abstract

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. Invitro 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 Rac1V12 and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3+ T-cell and gammadelta T-cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, indicating that PRN694 is an effective psoriasis therapeutic.

View details for PubMedID 29129599