Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin αvβ3
Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin αvβ3
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DOI：
10.1021/ja003579
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发表时间：
2001-02-21
影响因子：
15
通讯作者：
Cheresh, DA
中科院分区：
文献类型：
--
作者：
Boger, DL;Goldberg, J;Cheresh, DA
从现有的血管系统中生长出新的血管的过程，称为血管生成，对几种病理情况至关重要，最明显的是癌症。降解细胞外基质(ECM)的MMP2和促进内皮细胞附着ECM的整合素α(V)β(3)都参与了这一过程。最近的研究结果表明，MMP2基于其直接结合整合素α(V)β(3)的能力，以一种活性形式定位于侵袭内皮细胞表面，这表明破坏这种蛋白质-蛋白质相互作用可能是开发血管生成抑制剂的新靶点。小分子文库的筛选导致了在体外结合试验中破坏MMP2-α(V)β(3)相互作用的化合物的鉴定。进一步发现一种典型的抑制剂可以防止蛋白质基质的降解，而不直接抑制MMP2的活性，也不破坏α(V)β(3)与其经典的ECM配体Vitronectin的结合。该先导化合物的类似物和亚结构的合成和筛选使得能够鉴定抑制MMP2与α(V)β(3)结合所需的结构特征，这导致了一种更水溶性的衍生物的合成，它在体外保持了生物学特性，在体内具有强大的抗血管生成和抗肿瘤活性，证实了该靶点是一个有效的治疗干预靶点。
The process of new blood vessel growth from existing vasculature, known as angiogenesis, is critical to several pathological conditions, most notably cancer. Both MMP2, which degrades the extracellular matrix (ECM), and integrin alpha (v)beta (3), which contributes to endothelial cell attachment to the ECM, are critically involved in this process. Recent findings have shown that MMP2 is localized in an active form on the surface of invasive endothelial cells based on its ability to directly bind integrin alpha (v)beta (3), suggesting that disrupting this protein-protein interaction may represent a new target for the development of angiogenesis inhibitors. The screening of small molecule libraries led to the identification of compounds which disrupt the MMP2-alpha (v)beta (3) interaction in an in vitro binding assay. A prototypical inhibitor was further found to prevent the degradation of the protein matrix without directly inhibiting MMP2 activity or disrupting the binding of alpha (v)beta (3) to its classical ECM ligand, vitronectin. The synthesis and screening of analogues and substructures of this lead compound allowed the identification of requisite structural features for inhibition of MMP2 binding to alpha (v)beta (3) This led to the synthesis of a more water-soluble derivative which maintains the in vitro biological properties and has potent antiangiogenic and antitumor activity in vivo, validating the target as one useful for therapeutic intervention.