Abstract 2467: Development of new N-Arylbenzamides as STAT3 dimerization inhibitors

The association of aberrant STAT3 activation with many types of human malignancies and solid tumors makes STAT3 an attractive molecular target for the development of novel cancer therapeutics. STAT3 dimerization via two reciprocal phosphotyrosine (pTyr)-Src-homology 2 (SH2) interaction is required for its binding to specific DNA-response elements in the promoters of target genes. This dimerization process offers a potentially selective way to directly target STAT3. Nevertheless the design of small molecules capable of disrupting protein-protein interactions remains a significant challenge to medicinal chemistry. We describe the development of a new class of small molecule capable of disrupting the STAT3:STAT3 protein-protein interaction. We identified the STAT3 inhibitor S3I-201 (NSC-74859) from the NCI chemical collection by using structure-based virtual screening with a model based on the X-ray crystal structure of the STAT3β homodimer. We developed a series of phosphonic and salicylic acids based on the structure of S3I-201 incorporating an N-arylbenzamide scaffold. The series of phosphonic and salicylic acids with a shorter amide linker lacking the O-tosyl group has improved STAT3 inhibitory activity [as measured by a competitive, fluorescence-polarization (FP)-based assay]. The equivalent in vitro potencies observed by the replacement of phosphonic acid moiety of with 5-amino-2-hydroxybenzoic acid group validates 5-amino-2-hydroxybenzoic acid as a phosphotyrosine mimic in this series. The binding mode of selected compounds, as predicted by molecular modeling, will be discussed. Our docking studies indicated that the phosphonic and salicylic acid groups interact in the pTyr-705 binding site in a broadly similar manner, while the other substituents occupy the STAT3 pY+1 and pY-X hydrophobic pockets. One of the most potent compounds in vitro (in the FP assay) inhibits STAT3 dimerization in intact cells and suppresses malignant transformation in human cancer cells that depend on STAT3. The in vitro and cell based potency of the N-arylbenzamides warrants further development of this scaffold as STAT3 inhibitors. Citation Format: Nicholas J. Lawrence, Roberta Pireddu, Yiyu Ge, Murali K. Urlam, Xiaolei Zhang, Ying Sun, Harshani R. Lawrence, Wayne C. Guida, Said Sebti. Development of new N-Arylbenzamides as STAT3 dimerization inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Wash