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

TLDR

S3I‑201, a chemical probe inhibitor of Stat3, was identified through structure‑based virtual screening of National Cancer Institute libraries using a computer model of the Stat3 SH2 domain bound to its phosphotyrosine peptide derived from the crystal structure of the Stat3β homodimer. S3I‑201 blocks Stat3 dimerization, DNA binding, and transcription, inhibits growth and induces apoptosis in Stat3‑activated tumor cells, downregulates cyclin D1, Bcl‑xL, and survivin, suppresses breast tumor growth in vivo, and thus demonstrates antitumor activity mediated by Stat3 inhibition, supporting its clinical potential.

Abstract

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 Stat3β 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.