Department of Chemical and Physical Sciences, University of Toronto, 3359 Mississauga Road North, Mississauga, Ontario L5L 1C6, Canada.
Inorg Chem. 2012 Aug 6;51(15):8284-91. doi: 10.1021/ic3008393. Epub 2012 Jul 11.
Src Homology 2 (SH2) domains are the paradigm of phosphotyrosine (pY) protein recognition modules and mediate numerous cancer-promoting protein-protein complexes. Effective SH2 domain mimicry with pY-binding coordination complexes offers a promising route to new and selective disruptors of pY-mediated protein-protein interactions. We herein report the synthesis and in vitro characterization of a library of coordination complex SH2 domain proteomimetics. Compounds were designed to interact with phosphopeptides via a two-point interaction, principally with pY, and to make secondary interactions with pY+2/3, thereby achieving sequence-selective discrimination. Here, we report that lead mimetics demonstrated high target phosphopeptide affinity (K(a) ∼ 10(7) M(-1)) and selectivity. In addition, biological screening in various tumor cells for anticancer effects showed a high degree of variability in cytotoxicity among receptors, which supported the proposed two-point binding mode. Several receptors potently disrupted cancer cell viability in breast cancer, prostate cancer, and acute myeloid leukemia cell lines.
Src 同源性 2（SH2）结构域是磷酸酪氨酸（pY）蛋白识别模块的范例，介导许多促进癌症的蛋白-蛋白复合物。有效的 SH2 结构域模拟 pY 结合的协调配合物为新的和选择性的 pY 介导的蛋白-蛋白相互作用的破坏者提供了一个有希望的途径。本文报道了一个协调配合物 SH2 结构域拟肽库的合成和体外特性。化合物的设计目的是通过两点相互作用，主要是与 pY，与 pY+2/3 进行二次相互作用，从而实现序列选择性识别。在这里，我们报告说，先导模拟物表现出高靶磷酸肽亲和力（K(a)∼10(7)M(-1))和选择性。此外，在各种肿瘤细胞中进行的抗癌作用的生物筛选显示，在受体中细胞毒性的变异性很大，这支持了所提出的两点结合模式。几种受体在乳腺癌、前列腺癌和急性髓系白血病细胞系中强有力地破坏了癌细胞的活力。
