Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors

Psoriasis is characterized by hyperproliferation of keratinocytes associate d with an inflammatory infiltrate in the epidermis. Among factors which may be related to hyperplasia of psoriatic keratinocytes is the persistent aut ocrine stimulation of the epidermal growth factor receptor (EGFR) by transf orming growth factor-alpha. Owing to the pivotal role of the EGFR in drivin g the growth of human psoriatic keratinocytes, we examined two selective in hibitors of EGFR kinase activity: 4-(3-bromophenylamino)-6,7-dimethoxyquina zoline (AG1517/SU5271) and 4-(3-chlorophenylamino)-6, 7-dimethoxyquinazolin e (AG1478) on psoriatic keratinocytes. SU5271 potently inhibits ligand-indu ced autophosphorylation of EGFR, and downstream signal transduction events, including DNA replication and cell cycle progression, SU5271, at micromola r concentrations, inhibited the proliferation of keratinocytes isolated fro m psoriatic lesions in excellent correlation with its EGFR kinase inhibitor y activity in these cells, Biologically active concentrations of SU5271 pen etrated human cadaver skin, suggesting that this compound is a strong candi date as an antipsoriatic agent.