title: Alkylation of cysteine 468 in Stat3 defines a novel site for therapeutic development.
abstract: Stat3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in multiple cancers. Inhibition of Stat3 signaling pathways suppresses cell survival signals and leads to apoptosis in cancer cells, suggesting direct inhibition of Stat3 function is a viable therapeutic approach. Herein, we identify a small molecule, C48, as a selective Stat3-family member inhibitor. To determine its mechanism of action, we used site-directed mutagenesis and multiple biochemical techniques to show that C48 alkylates Cys468 in Stat3, a residue at the DNA-binding interface. We further demonstrate that C48 blocks accumulation of activated Stat3 in the nucleus in tumor cell lines that overexpress active Stat3, leading to impressive inhibition of tumor growth in mouse models. Collectively, these findings suggest Cys468 in Stat3 represents a novel site for therapeutic intervention and demonstrates the promise of alkylation as a potentially effective chemical approach for Stat3-dependent cancers.
authors.affiliation: Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Renzo
authors.initials: R
authors.lastname: Corzano
authors.forename: Rumana
authors.initials: R
authors.lastname: Rashid
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
authors.forename: Maheswari
authors.initials: M
authors.lastname: Senthil
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Anne
authors.initials: A
authors.lastname: Schroeder
authors.forename: Allen
authors.initials: A
authors.lastname: Mao
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: John
authors.initials: J
authors.lastname: Yim
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yakushijin
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yakushijin
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Vaidehi
authors.forename: Roger
authors.initials: R
authors.lastname: Moore
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gugiu
authors.forename: Terry D
authors.initials: TD
authors.lastname: Lee
authors.forename: Richard
authors.initials: R
authors.lastname: Yip
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.forename: John C
authors.initials: JC
authors.lastname: Williams
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D053613:Janus Kinase 1 / Q000187:drug effects; D053614:Janus Kinase 2 / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D004268:DNA-Binding Proteins; C560797:NSC 368262; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D003545:Cysteine