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

  • J Med Chem. 2013 May 23;56(10):4125-9. doi: 10.1021/jm400397x.
Stephen S Scully  1 ,  Alicia J Tang ,  Morten Lundh ,  Carrie M Mosher ,  Kedar M Perkins ,  Bridget K Wagner
Affiliations
  • 1. Chemical Biology Program and Chemical Biology Platform, The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
PMID: 23617753 DOI: 10.1021/jm400397x
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.