TYRPHOSTINS .3. STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF ALPHA-SUBSTITUTED BENZYLIDENEMALONONITRILE 5-S-ARYLTYRPHOSTINS

In this study we describe an extension of our previous studies on cis- benzylidenemalononitrile tyrphostins. We have introduced S-aryl substi tuents in the 5 position (meta vis-a-vis the malononitrile moiety). We find that these compounds are potent blockers of EGFR kinase and its homolog HER-2 kinase. Interestingly, we find that certain S-aryltyrpho stins discriminate between EGFR and HER-2 kinase in favor of the HER-2 kinase domain by almost 2 orders of magnitude. When examined in intac t cells it was found that these selective S-aryltyrphostins are equipo tent in inhibiting EGF dependent proliferation of NIH 3T3 harboring ei ther the EGF receptor or the chimera EGF/neu (HER1-2). These findings suggest that the antiproliferative activity of these tyrphostins is ma inly due to the inhibition of a mitogenic signaling element downstream to the growth receptor kinase.