title: A novel small-molecule disrupts Stat3 SH2 domain-phosphotyrosine interactions and Stat3-dependent tumor processes.
abstract: The molecular modeling of the phosphotyrosine (pTyr)-SH2 domain interaction in the Stat3:Stat3 dimerization, combined with in silico structural analysis of the Stat3 dimerization disruptor, S3I-201, has furnished a diverse set of analogs. We present evidence from in vitro biochemical and biophysical studies that the structural analog, S3I-201.1066 directly interacts with Stat3 or the SH2 domain, with an affinity (K(D)) of 2.74microM, and disrupts the binding of Stat3 to the cognate pTyr-peptide, GpYLPQTV-NH(2), with an IC(50) of 23microM. Moreover, S3I-201.1066 selectively blocks the association of Stat3 with the epidermal growth factor receptor (EGFR), and inhibits Stat3 tyrosine phosphorylation and nuclear translocation in EGF-stimulated mouse fibroblasts. In cancer cells that harbor aberrant Stat3 activity, S3I-201.1066 inhibits constitutive Stat3 DNA-binding and transcriptional activities. By contrast, S3I-201.1066 has no effect on Src activation or the EGFR-mediated activation of the Erk1/2(MAPK) pathway. S3I-201.1066 selectively suppresses the viability, survival, and malignant transformation of the human breast and pancreatic cancer lines and the v-Src-transformed mouse fibroblasts harboring persistently active Stat3. Treatment with S3I-201.1066 of malignant cells harboring aberrantly active Stat3 down-regulated the expression of c-Myc, Bcl-xL, Survivin, the matrix metalloproteinase 9, and VEGF. The in vivo administration of S3I-201.1066-induced significant antitumor response in mouse models of human breast cancer, which correlates with the inhibition of constitutively active Stat3 and the suppression of known Stat3-regulated genes. Our studies identify a novel small-molecule that binds with a high affinity to Stat3, blocks Stat3 activation and function, and thereby induces antitumor response in human breast tumor xenografts harboring persistently active Stat3.
authors.affiliation: University of Central Florida College of Medicine, Orlando, 32827, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.forename: James
authors.initials: J
authors.lastname: Turkson
mesh_terms: D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000503:physiopathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D005260:Female; D016231:Fluorescence Polarization Immunoassay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020349:Surface Plasmon Resonance; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D018909:src Homology Domains / Q000187:drug effects* / Q000502:physiology
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; D004273:DNA, Neoplasm; C520337:NSC 74859; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D066246:ErbB Receptors