title: Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain.
abstract: Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i)=13 μM), inhibited Stat3-Stat3 protein interactions (IC(50)=19 μM) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50)=10 and 16 μM, respectively).
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, Canada L5L 1C6.
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Sumaiya
authors.initials: S
authors.lastname: Sharmeen
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020156:Salicylic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018909:src Homology Domains / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D054852:Small Molecule Libraries; D020156:Salicylic Acid