GENISTEIN ANALOGS - EFFECTS ON EPIDERMAL GROWTH-FACTOR RECEPTOR TYROSINE KINASE AND ON STRESS-ACTIVATED PATHWAYS

Two genistein analogues (MD831 and MD833) have been synthesized and an alyzed for their biological properties and their mechanism of action i n comparison to genistein either in vitro or in intact cells. We showe d that, in vitro, one of these compounds (MD831) inhibits the tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) as efficiently as genistein. However, treatment of A431 cells w ith these compounds did not result in any significant modification of EGFR tyrosine phosphorylation. Extracellular-signal regulated kinase ( ERK) phosphorylation in cells stimulated by EGF was enhanced in the pr esence of MD831, whereas the other compounds, genistein and MD833, wer e able to activate the c-jun N-terminal kinase (JNK). This study showe d that two structurally related compounds could elicit markedly differ ent pharmacological effects on two signalling pathways, one involved i n the mitogenic response and the other in the stress response. Such co mpounds may be useful to characterize signalling events involved in ce ll response to physiological stimuli.