Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity

S3I-201 (NSC 74859) is a chemical probe inhibitor of STAT3 activity, which was identified from the National Cancer Institute chemical libraries by using structure-based virtual screening with a computer model of the STAT3 SH2 domain bound to its STAT3 phosphotyrosine peptide derived from the x-ray crystal structure of the Stat3beta homodimer. S3I-201 inhibits STAT3.STAT3 complex formation and STAT3 DNA-binding and transcriptional activities. Furthermore, S3I-201 inhibits growth and induces Apoptosis preferentially in tumor cells that contain persistently activated STAT3. Constitutively dimerized and active Stat3C and STAT3 SH2 domain rescue tumor cells from S3I-201-induced Apoptosis. Finally, S3I-201 inhibits the expression of the Stat3-regulated genes encoding cyclin D1, Bcl-xL, and Survivin and inhibits the growth of human breast tumors in vivo. These findings strongly suggest that the antitumor activity of S3I-201 is mediated in part through inhibition of aberrant STAT3 activation and provide the proof-of-concept for the potential clinical use of STAT3 inhibitors such as S3I-201 in tumors harboring aberrant STAT3.