Acquisition of high-affinity, SH2-targeted ligands via a spatially focused library
Acquisition of high-affinity, SH2-targeted ligands via a spatially focused library
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DOI：
10.1021/jm980663f
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发表时间：
1999-03-11
影响因子：
7.3
通讯作者：
Lawrence, DS
中科院分区：
文献类型：
--
作者：
Lee, TR;Lawrence, DS
导论. Src 1同源性2（SH 2）结构域是许多信号转导蛋白的组成部分，在组织连贯的信号级联中起着关键作用。[2]当一个蛋白质中包含磷酸酪氨酸的一级序列被另一个蛋白质的SH 2结构域识别并与其协调时，后者发生。SH 2靶向药物的设计受到了相当大的关注，因为这些物种可能会破坏已知导致各种疾病状态的信号通路。3通常，SH 2结构域对含磷酸酪氨酸的肽的亲和力（即KD）在200-800 nM范围内（例外情况见下文）。4非肽类SH 2靶向化合物也有描述，但这些物质对SH 2结构域的亲和力通常比肽类化合物低1-3个数量级。5最近，一些研究表明，非天然基序，当附加到活性位点定向肽，可以显着提高这类信号转导元件的蛋白激酶6和SH 3结构域的亲和力和选择性。7我们在本文中描述了肽/非肽缀合物的获得，这些缀合物是迄今为止报道的最紧密结合和最具选择性的SH 2靶向剂。8，9我们最初的研究集中在获得靶向Lck 1和Fyn 1的SH 2结构域的化合物，已知Src酪氨酸激酶家族成员参与T细胞活化。10与其他Src酪氨酸激酶一样，Lck和Fyn的SH 2结构域对序列-磷酸化Tyr-Glu-Glu-Ile-表现出相同的偏好，11其中SH 2亲和力强烈依赖于磷酸化Tyr和Ile侧链。2b有趣的是，结构和生物化学研究表明，位于磷酸化Tyr的N-末端的常规氨基酸残基对SH 2选择性或亲和力几乎没有影响。2b尽管有后一种观察结果，但SH 2表面的疏水性凹陷确实位于SH 2结合肽中磷酸Tyr的胺附近（图1）。因此，这种内陷可以作为一个潜在的结合位点的结构相容的配体附加关闭的N-末端的磷酸Tyr-Glu-Glu-Ile-酰胺。由于推定的结合区域的大小是适度的，因此几乎没有机会通过串联连接的亚基阵列的组合合并来产生广泛的分子多样性。相反，我们开发了一种并行合成策略（方案1），
Introduction. The Src1 homology 2 (SH2) domain, a component of many signal-transducing proteins, plays a critical role in organizing coherent signaling cascades. 2 The latter transpires when primary sequences encompassing phosphotyrosine in one protein are recognized by and coordinate to the SH2 domain of a second. The design of SH2-targeted agents has received considerable attention since such species could disrupt signaling pathways known to be responsible for a variety of disease states. 3 In general, the affinity (ie, KD) of SH2 domains for phosphotyrosine-containing peptides lies in the range of 200-800 nM (for an exception vide infra). 4 Nonpeptidic SH2-targeted compounds have also been described, but the affinity of these species for SH2 domains is typically 1-3 orders of magnitude less than that displayed by their peptidic counterparts. 5 Recently, several studies have shown that unnatural motifs, when appended to active site-directed peptides, can dramatically enhance both the affinity and selectivity for such signal-transducing elements as protein kinases6 and SH3 domains. 7 We describe herein the acquisition of peptide/nonpeptide conjugates that are among the tightest binding and most selective SH2-targeted agents reported to date. 8, 9Our initial studies have focused on the acquisition of compounds that target the SH2 domains of Lck1 and Fyn1, Src tyrosine kinase family members known to participate in T cell activation. 10 Like other Src tyrosine kinases, the SH2 domains of Lck and Fyn exhibit an identical preference for the sequence-phosphoTyr-Glu-Glu-Ile-, 11 where SH2 affinity is strongly dependent upon the phosphoTyr and Ile side chains. 2b Interestingly, structural and biochemical studies indicate that conventional amino acid residues positioned to the N-terminus of phosphoTyr have little influence on either SH2 selectivity or affinity. 2b Despite the latter observation, a hydrophobic indentation in the SH2 surface does lie adjacent to the amine of phosphoTyr in an SH2-bound peptide (Figure 1). Consequently, this invagination could serve as a potential binding site for a structurally compatible ligand appended off the N-terminus of phosphoTyr-Glu-Glu-Ile-amide. Since the size of the putative binding region is modest, there is little opportunity to create extensive molecular diversity via a combinatorial amalgamation of an array of subunits connected in series. Instead, we developed a parallel synthesis strategy (Scheme 1) that achieves a