The Discovery of Phenylbenzamide Derivatives as Grb7-Based Antitumor Agents
The Discovery of Phenylbenzamide Derivatives as Grb7-Based Antitumor Agents
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DOI：
10.1002/cmdc.201200400
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发表时间：
2013-02-01
期刊：
影响因子：
3.4
通讯作者：
Wilce, Jacqueline A.
中科院分区：
文献类型：
--
作者：
Ambaye, Nigus D.;Gunzburg, Menachem J.;Wilce, Jacqueline A.
Grb7是一种非催化蛋白，其过度表达与癌细胞的增殖和迁移潜能有关。虚拟筛选策略包括基于形状的相似性搜索、分子对接和2D相似性搜索以及实验结合研究(热流和等温滴定热法)，结果鉴定了Grb7 SH2结构域的9个新的苯基苯甲酰胺拮抗剂。观察到中等的结合亲和力，从苯基苯甲酰胺NSC？104999(1)的Kd=32.3u M到结构相关的化合物NSC？57148(2)的Kd=1.1u M。将亲和力数据反卷积到其组分中，揭示了铅结合的不同，从基于熵的(铅1)到热驱动的(NSC？100874(3)、NSC？55158(4)和化合物2)。最后，我们发现先导化合物1能够抑制乳腺癌细胞的生长，其IC50值为39.9微米。这些结构有望成为基于Grb7的抗癌药物开发的新先导化合物。
Grb7 is a non-catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells. Virtual screening strategies involving a shape-based similarity search, molecular docking, and 2D-similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide-based antagonists of the Grb7 SH2 domain. Moderate binding affinities were observed, ranging from Kd=32.3 mu M for lead phenylbenzamide NSC?104999 (1) to Kd=1.1 mu M for a structurally related compound, NSC?57148 (2). Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1) to enthalpically driven (NSC?100874 (3), NSC?55158 (4), and compound 2). Finally, the lead compound 1 was found to decrease the growth of MDA-MB-468 breast cancer cells, with an IC50 value of 39.9 mu M. It is expected that these structures will serve as novel leads in the development of Grb7-based anticancer therapeutics.