Tyrphostins. 3. Structure—Activity Relationship Studies of α-Substituted Benzylidenemalononitrile 5-S-Aryltyrphostins

Aviv Gazit, Nir Osherov, Israel Posner, Allan Bar-Sinai, Chaim Gilon, Alexander Levitzki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

In this study we describe an extension of our previous studies on cis-benzylidenemalononitrile tyrphostins. We have introduced S-aryl substituents 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-aryltyrphostins discriminate between EGFR and HER-2 kinase in favor of the HER-2 kinase domain by almost 2 orders of magnitude. When examined in intact cells it was found that these selective S-aryltyrphostins are equipotent in inhibiting EGF dependent proliferation of NIH 3T3 harboring either the EGF receptor or the chimera EGF/neu (HER1-2). These findings suggest that the antiproliferative activity of these tyrphostins is mainly due to the inhibition of a mitogenic signaling element downstream to the growth receptor kinase.

Original languageEnglish
Pages (from-to)3556-3564
Number of pages9
JournalJournal of Medicinal Chemistry
Volume36
Issue number23
DOIs
StatePublished - 1993

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