Dayam Raveendra, Aiello Francesca, Deng Jinxia, Wu Yun, Garofalo Antonio, Chen Xiaoyuan, Neamati Nouri
Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90033, USA.
J Med Chem. 2006 Jul 27;49(15):4526-34. doi: 10.1021/jm051296s.
Integrin alphavbeta3 has been implicated in multiple aspects of tumor progression and metastasis. Many tumors have high expression of alphavbeta3 that correlates with tumor progression. Therefore, alphavbeta3 receptor is an excellent target for drug design and delivery. We have discovered a series of novel alphavbeta3 antagonists utilizing common feature pharmacophore models. Upon validation using a database of known alphavbeta3 receptor antagonists, a highly discriminative pharmacophore model was used as a 3D query. A search of a database of 600 000 compounds using the pharmacophore Hypo5 yielded 832 compounds. On the basis of structural novelty, 29 compounds were tested in alphavbeta3 receptor specific binding assay and four compounds showed excellent binding affinity. A limited SAR analysis on the active compound 26 resulted in the discovery of two compounds with nanomolar to subnanomolar binding affinity. These small-molecule compounds could be conjugated to paclitaxel for selective delivery to alphavbeta3 positive metastatic cancer cells.
整合素αvβ3与肿瘤进展和转移的多个方面有关。许多肿瘤中αvβ3表达较高，这与肿瘤进展相关。因此，αvβ3受体是药物设计和递送的理想靶点。我们利用共同特征药效团模型发现了一系列新型αvβ3拮抗剂。在使用已知αvβ3受体拮抗剂数据库进行验证后，一个具有高度区分性的药效团模型被用作三维查询。使用药效团Hypo5对一个包含600000种化合物的数据库进行搜索，得到了832种化合物。基于结构新颖性，对29种化合物进行了αvβ3受体特异性结合试验，其中4种化合物表现出优异的结合亲和力。对活性化合物26进行的有限构效关系分析导致发现了两种具有纳摩尔至亚纳摩尔结合亲和力的化合物。这些小分子化合物可以与紫杉醇偶联，用于选择性递送至αvβ3阳性转移性癌细胞。
