Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

[Buddhahead]

Down-regulation of NF-?B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition in The Journal of Biological Chemistry, Guangtao Zhang, Ruijie Liu, Yifei Zhong, Alexander N. Plotnikov, Weijia Zhang, Lei Zeng, Elena Rusinova, Guillermo Gerona-Nevarro, Natasha Moshkina, Jennifer Joshua, Peter Y. Chuang, Michael Ohlmeyer, John Cijiang He and Ming-Ming Zhou*, Mount Sinai School of Medicine, United States, May 2012

Abstract:
"NF-kB-mediated inflammation is the major pathology in chronic diseases including HIV-associated kidney disease (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in kidney induces NF-kB activation leading to the production of pro-inflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kB transcriptional activity by pharmacological blocking NF-kB binding to the transcriptional cofactor BRD4 that is required for the assembly of the productive transcriptional complex comprising p-TEFb and RNA Polymerase II. We showed that our BET-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-kB, effectively attenuates NF-kB transcriptional activation of pro-inflammatory genes in kidney cells treated with TNFa or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at NF-kB pro-inflammatory activity, represents a new therapeutic approach for treating NF-?B-mediated inflammation and kidney injury in HIVAN.

Article at:
http://www.jbc.org/content/early/2012/05/29/jbc.M112.359505