Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
Principia Biopharma, South San Francisco, California, USA.
J Invest Dermatol. 2018 Apr;138(4):864-871. doi: 10.1016/j.jid.2017.10.029. Epub 2017 Nov 10.
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 and imiquimod mouse models of psoriasis. PRN694 also inhibited CD3 T-cell and γδ T-cell infiltration into skin regions. Inhibition of ITK and RLK attenuated psoriasis-associated signaling pathways, indicating that PRN694 is an effective psoriasis therapeutic.
慢性且普遍存在的皮肤疾病银屑病的特征是表皮过度增殖和异常的免疫活性。许多研究强调了分化 T 淋巴细胞在银屑病进展中的作用。目前有许多针对 T 淋巴细胞产生的促炎细胞因子的生物制剂，但仍需要改进治疗方法。小分子 PRN694 与 ITK 和 RLK 共价结合，这两种 Tec 激酶在 T 淋巴细胞激活的下游被激活，在银屑病皮肤中均上调。这些 Tec 激酶参与介导 T 淋巴细胞增殖、分化和迁移以及促炎细胞因子产生的信号级联反应。体外分析表明，PRN694 可有效抑制小鼠 Th17 分化 T 淋巴细胞产生的 IL-17A。此外，PRN694 还能有效减轻 Rac1 和咪喹莫特诱导的银屑病小鼠模型的银屑病样表型严重程度，并减少表皮增殖和厚度。PRN694 还抑制 CD3 T 细胞和 γδ T 细胞浸润到皮肤区域。抑制 ITK 和 RLK 可减弱与银屑病相关的信号通路，表明 PRN694 是一种有效的银屑病治疗药物。
