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

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 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.

• Authors: Khandaker Siddiquee, Shumin Zhang, Wayne C Guida, Michelle A Blaskovich, Benjamin Greedy, Harshani R Lawrence, M L Richard Yip, Richard Jove, Mark M McLaughlin, Nicholas J Lawrence, Said M Sebti, James Turkson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 18 Pg. 7391-6 (May 01 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17463090 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aminosalicylic Acids
• Antineoplastic Agents
• Benzenesulfonates
• NSC 74859
• STAT3 Transcription Factor
• Phosphotyrosine
• Aminosalicylic Acid
• DNA

Topics

• Aminosalicylic Acid (chemistry, metabolism, therapeutic use)
• Aminosalicylic Acids
• Animals
• Antineoplastic Agents (chemistry, metabolism, therapeutic use)
• Apoptosis
• Benzenesulfonates (chemistry, metabolism, therapeutic use)
• Cell Line
• Computational Biology
• DNA (chemistry, metabolism)
• Drug Evaluation, Preclinical
• Gene Expression Regulation
• Humans
• Mice
• Models, Molecular
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phosphotyrosine (metabolism)
• Protein Binding
• Protein Structure, Tertiary
• STAT3 Transcription Factor (antagonists & inhibitors, chemistry, genetics, metabolism)
• Transcription, Genetic (genetics)
• Xenograft Model Antitumor Assays