Gazit A, Osherov N, Gilon C, Levitzki A
Department of Organic Chemistry, The Institute of Chemistry and Life Sciences, The Hebrew University of Jerusalem, Israel.
J Med Chem. 1996 Dec 6;39(25):4905-11. doi: 10.1021/jm960225d.
Benzylidenemalononitrile (BMN) tyrphostins were previously found to be potent inhibitors of EGF receptor (EGFR) tyrosine kinase activity. Since these compounds were found to compete for the substrate and sometimes with the ATP site and since EGFR acts as a dimer, we prepared a series of dimeric tyrphostins. These dimeric tyrphostins were built from two BMN units linked by various spacers and designed to fit the dimeric cross-autophosphorylation signal transduction intermediate of the EGFR tyrosine kinases. Structure-activity relationship of these potent dimeric EGF receptor tyrosine kinase inhibitors is reported.
亚苄基丙二腈（BMN）酪氨酸磷酸化抑制剂先前被发现是表皮生长因子受体（EGFR）酪氨酸激酶活性的有效抑制剂。由于发现这些化合物会竞争底物，有时还会与ATP位点竞争，并且由于EGFR以二聚体形式发挥作用，我们制备了一系列二聚体酪氨酸磷酸化抑制剂。这些二聚体酪氨酸磷酸化抑制剂由两个通过各种间隔基连接的BMN单元构建而成，设计用于适配EGFR酪氨酸激酶的二聚体交叉自磷酸化信号转导中间体。本文报道了这些强效二聚体表皮生长因子受体酪氨酸激酶抑制剂的构效关系。
