Development of newN-Arylbenzamides as STAT3 Dimerization Inhibitors.
TheO-tosylsalicylamideS3I-201(10) was used as a starting point for design and synthesis of novel STAT-3 dimerization inhibitors with improved drug-like qualities. The phosphonic acid12dand salicylic acids13f,13gwith a shorter amide linker lacking theO-tosyl group had improved STAT-3 inhibitory activity. The equivalent potencies observed by the replacement of phosphonic acid moiety of12dwith 5-amino-2-hydroxybenzoic acid group as in13ffurther validates 5-amino-2-hydroxybenzoic acid as a phosphotyrosine mimic. The salicylic acid13fdisplayed improved whole cell activity. The focused library of salicylic acids13with benzamide linker indicated that hydrophobic heptyl and cyclohexyl are the best tolerated R groups and a biphenyl ether (as the Ar group) significantly contributes to STAT3 inhibitory activity. Our docking studies indicated that the acidic groups of12d,13fand13ginteract in the p-Tyr-705 binding site in a broadly similar manner, while the phenoxybenzoyl group and the cyclohexylbenzyl group occupying pY+1 and pY-X hydrophobic pockets respectively. Thein vitroand cell based potency of13fwarrants further development of this scaffold as STAT3 inhibitors.
Departments of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Murali K
MK
Urlam
Roberta
R
Pireddu
Yiyu
Y
Ge
Xiaolei
X
Zhang
Ying
Y
Sun
Harshani R
HR
Lawrence
Wayne C
WC
Guida
Saïd M
SM
Sebti
Nicholas J
NJ
Lawrence