The Discovery of Phenylbenzamide Derivatives as Grb7-Based Antitumor Agents

• Published in: ChemMedChem Vol. 8; no. 2; pp. 280 - 288
• Main Authors: Ambaye, Nigus D., Gunzburg, Menachem J., Lim, Reece C. C., Price, John T., Wilce, Matthew C. J., Wilce, Jacqueline A.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.02.2013; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzamides - chemistry; Benzamides - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Calorimetry; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Grb7; GRB7 Adaptor Protein - antagonists & inhibitors; GRB7 Adaptor Protein - chemistry; GRB7 Adaptor Protein - metabolism; Humans; Medical research; Molecular Docking Simulation; phenylbenzamides; SH2 domain; src Homology Domains - drug effects; virtual screening
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.201200400

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 μM for lead phenylbenzamide NSC 104999 (1) to Kd=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 IC50 value of 39.9 μM. It is expected that these structures will serve as novel leads in the development of Grb7‐based anticancer therapeutics. Stopping tumor progression: Virtual screening involving a shape‐based similarity search, molecular docking, and 2D‐similarity searches complemented by experimental binding studies resulted in the discovery of phenylbenzamide ligands that are able to interact with the Grb7 SH2 domain and inhibit the growth of MDA‐MB‐468 cancer cells. The NSC 104999 lead is shown along with its predicted binding mode at the surface of Grb7.