Biochemistry and Molecular Biology, Monash University, Wellington Road, VIC 3800, Australia.
ChemMedChem. 2013 Feb;8(2):280-8. doi: 10.1002/cmdc.201200400. Epub 2012 Dec 17.
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 K(d)=32.3 μM for lead phenylbenzamide NSC 104999 (1) to K(d)=1.1 μM 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 IC(50) value of 39.9 μM. It is expected that these structures will serve as novel leads in the development of Grb7-based anticancer therapeutics.
Grb7 是一种非催化蛋白，其过表达与癌细胞的增殖和迁移潜力有关。涉及基于形状的相似性搜索、分子对接以及通过实验结合研究（Thermofluor 和等温滴定量热法）补充的 2D 相似性搜索的虚拟筛选策略，导致了九个新型基于苯基苯甲酰胺的 Grb7 SH2 结构域拮抗剂的鉴定。观察到中等结合亲和力，范围从 K(d)=32.3 μM 的先导苯基苯甲酰胺 NSC 104999（1）到 K(d)=1.1 μM 的结构相关化合物 NSC 57148（2）。将亲和力数据分解为其组成部分，揭示了先导化合物结合的差异，从基于熵的（先导化合物 1）到焓驱动的（NSC 100874（3）、NSC 55158（4）和化合物 2）。最后，发现先导化合物 1 可降低 MDA-MB-468 乳腺癌细胞的生长，IC(50) 值为 39.9 μM。预计这些结构将作为基于 Grb7 的抗癌治疗开发的新型先导化合物。
