title: Isoform selective inhibition of STAT1 or STAT3 homo-dimerization via peptidomimetic probes: structural recognition of STAT SH2 domains.
abstract: The identification of constitutively activated STAT (Signal Transducers and Activators of Transcription) proteins in aberrant cell signaling pathways has led to investigations targeting the selective disruption of specific STAT isoforms directly associated with oncogenisis. We have identified, through the design of a library of peptidomimetic inhibitors, agents that selectively disrupt STAT1 or STAT3 homo-dimerization at low micromolar concentrations. ISS840 has 20-fold higher inhibition of STAT1 homo-dimerization (IC(50) value of 31 microM) relative to STAT3 (IC(50) value of 560 microM).
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.forename: William P
authors.initials: WP
authors.lastname: Katt
authors.forename: Matthew
authors.initials: M
authors.lastname: Glenn
authors.forename: Khandaker
authors.initials: K
authors.lastname: Siddiquee
authors.forename: Khandaker
authors.initials: K
authors.lastname: Siddique
authors.forename: Joon S
authors.initials: JS
authors.lastname: Kim
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D050794:STAT1 Transcription Factor / Q000737:chemistry*; D050795:STAT2 Transcription Factor / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000737:chemistry*; D018909:src Homology Domains
chemical_list: D010455:Peptides; D020033:Protein Isoforms; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494087:Stat3 protein, mouse