Inhibitors of tyrosine kinases in the treatment of psoriasis.

Psoriasis is a heterogenous skin disease, characterized by epidermal hyperproliferation, abnormal keratinization and inflammation. The heterogeneity of the disease results probably from the interaction of multiple gene abnormalities with environmental factors. The new approaches to drug design have become refocused to the emerging understanding of the role of signaling pathways in health and disease. Protein tyrosine kinases (PTKs) regulate cell proliferation, differentiation and immune processes. Uncontrolled signaling from receptor and intracellular tyrosine kinases can lead to numerous proliferative diseases: cancer, leukemia, restenosis and psoriasis. Identification of PTKs that play a key role in a defined disease can lead to a selective drug. The balance of signals which regulate the homeostasis of normal epidermis is altered in psoriasis. Several lines of evidence suggest a role for the EGF receptor system in this process. Therefore, blockers of the EGFR kinase were suggested as potent antipsoriasis agents. PTK inhibitors from the tyrphostin family were found to block EGF - dependent cell proliferation. AG 1571 (SU 5271) potently inhibits ligand-induced autophosphorylation of EGF-R, downstream signal transduction events, DNA replication and cell cycle progression at micromolar concentrations, as well as proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. AG 1571 (SU 5271) has been in clinical trials by SUGEN Inc. since early 1997. Overexpression of the EGFR is the hallmark of most epithelial cancers. Therefore one can view blockers of the EGFR kinase as becoming universal inhibitors. Tyrphostins are the first signal transduction agents to be used in the clinic. This article summarizes recent progress in the development of PTK inhibitors in the treatment of psoriasis.