Development of new N-arylbenzamides as STAT3 dimerization inhibitors

Abstract

The <i>O</i>-tosylsalicylamide <b>S3I-201</b> (<b>10</b>) was used as a starting point for design and synthesis of novel STAT-3 dimerization inhibitors with improved drug-like qualities. The phosphonic acid <b>12d</b> and salicylic acids <b>13f</b>, <b>13g</b> with a shorter amide linker lacking the <i>O</i>-tosyl group had improved STAT-3 inhibitory activity. The equivalent potencies observed by the replacement of phosphonic acid moiety of <b>12d</b> with 5-amino-2-hydroxybenzoic acid group as in <b>13f</b> further validates 5-amino-2-hydroxybenzoic acid as a phosphotyrosine mimic. The salicylic acid <b>13f</b> displayed improved whole cell activity. The focused library of salicylic acids <b>13</b> with 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 of <b>12d</b>, <b>13f</b> and <b>13g</b> interact 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. The <i>in vitro</i> and cell based potency of <b>13f</b> warrants further development of this scaffold as STAT3 inhibitors.