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.
Siddiquee
Khandaker
K
BioMolecular Science Center, University of Central Florida, Orlando, FL 32826, USA.
Zhang
Shumin
S
Guida
Wayne C
WC
Blaskovich
Michelle A
MA
Greedy
Benjamin
B
Lawrence
Harshani R
HR
Yip
M L Richard
ML
Jove
Richard
R
McLaughlin
Mark M
MM
Lawrence
Nicholas J
NJ
Sebti
Said M
SM
Turkson
James
J
D010131:Aminosalicylic Acid / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D000636:Aminosalicylic Acids; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis; D001557:Benzenesulfonates / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D002460:Cell Line; D019295:Computational Biology; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C520337:NSC 74859; D050796:STAT3 Transcription Factor; D019000:Phosphotyrosine; D010131:Aminosalicylic Acid; D004247:DNA