Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors.
Psoriasis is characterized by hyperproliferation of keratinocytes associated with an inflammatory infiltrate in the epidermis. Among factors which may be related to hyperplasia of psoriatic keratinocytes is the persistent autocrine stimulation of the epidermal growth factor receptor (EGFR) by transforming growth factor-alpha. Owing to the pivotal role of the EGFR in driving the growth of human psoriatic keratinocytes, we examined two selective inhibitors of EGFR kinase activity: 4-(3-bromophenylamino)-6, 7-dimethoxyquinazoline (AG1517/SU5271) and 4-(3-chlorophenylamino)-6, 7-dimethoxyquinazoline (AG1478) on psoriatic keratinocytes. SU5271 potently inhibits ligand-induced autophosphorylation of EGFR, and downstream signal transduction events, including DNA replication and cell cycle progression. SU5271, at micromolar concentrations, inhibited the proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. Biologically active concentrations of SU5271 penetrated human cadaver skin, suggesting that this compound is a strong candidate as an antipsoriatic agent.
Powell
T J
TJ
SUGEN, Inc; Redwood City, CA 94063, USA.
Ben-Bassat
H
H
Klein
B Y
BY
Chen
H
H
Shenoy
N
N
McCollough
J
J
Narog
B
B
Gazit
A
A
Harzstark
Z
Z
Chaouat
M
M
Levitzki
R
R
Tang
C
C
McMahon
J
J
Shawver
L
L
Levitzki
A
A
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004817:Epidermis / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D011565:Psoriasis / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology*; D012869:Skin Absorption; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
C108081:AG 1517; D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors