The discovery of phenylbenzamide derivatives as Grb7-based antitumor agents.
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.
Biochemistry and Molecular Biology, Monash University, Wellington Road, VIC 3800, Australia.
Nigus D
ND
Ambaye
Menachem J
MJ
Gunzburg
Reece C C
RC
Lim
John T
JT
Price
Matthew C J
MC
Wilce
Jacqueline A
JA
Wilce
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051382:GRB7 Adaptor Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D018909:src Homology Domains / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D051382:GRB7 Adaptor Protein