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J Med Chem DOI:10.1021/jm400397x

Small-molecule inhibitors of cytokine-mediated STAT1 signal transduction in β-cells with improved aqueous solubility.

Publication TypeJournal Article
Year of Publication2013
AuthorsScully, SS, Tang, AJ, Lundh, M, Mosher, CM, Perkins, KM, Wagner, BK
JournalJ Med Chem
Date Published2013 May 23
KeywordsAniline Compounds, Apoptosis, Blotting, Western, Caspase 3, Caspase 7, Cell Line, Chemistry, Pharmaceutical, Cytokines, Humans, Indicators and Reagents, Insulin-Secreting Cells, Interferon-gamma, Phosphorylation, Signal Transduction, Solubility, STAT1 Transcription Factor, Structure-Activity Relationship, Thermodynamics, Urea

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.


Alternate JournalJ. Med. Chem.
PubMed ID23617753
PubMed Central IDPMC3690275
Grant ListDP2 DK083048 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States