title: Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in β-cells with improved aqueous solubility.
abstract: We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced β-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-γ.
authors.affiliation: Chemical Biology Program and Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Scully
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Tang
authors.forename: Morten
authors.initials: M
authors.lastname: Lundh
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Mosher
authors.forename: Kedar M
authors.initials: KM
authors.lastname: Perkins
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007202:Indicators and Reagents; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D016207:Cytokines; D007202:Indicators and Reagents; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D014508:Urea; D053148:Caspase 3; D053179:Caspase 7