Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity
Abbreviated Journal Title
Proc. Natl. Acad. Sci. U. S. A.
DNA-BINDING ACTIVITY; CANCER-CELLS; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTOR; SIGNAL TRANSDUCER; MOLECULAR TARGETS; ACCURATE; DOCKING; GENE-REGULATION; APOPTOSIS; SRC; Multidisciplinary Sciences
S31-201 (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 Stat3 beta homodimer. S31-201 inhibits Stat3-Stat3 complex formation and Stat3 DNA-binding and transcriptional activities. Furthermore, S31-201 inhibits growth and induces apoptosis preferentially in tumor cells that contain persistently activated Stat3. Constitutively climerized and active Stat3C and Stat3 SH2 domain rescue tumor cells from S31-201-induced apoptosis. Finally, S31-201 inhibits the expression of the Stat3-regulated genes encoding cyclin D1, BcI-xL, and survivin and inhibits the growth of human breast tumors in vivo. These findings strongly suggest that the antitumor activity of S31-201 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 S31-201 in tumors harboring aberrant Stat3.
Proceedings of the National Academy of Sciences of the United States of America
"Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity" (2007). Faculty Bibliography 2000s. 7653.