Minimum structural requirements for inhibitors of the zinc finger protein TRAF6. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Radwan, Mohamed O.; Koga, Ryoko; Hida, Tomohiro; Ejima, Tomohiko; Kanemaru, Yosuke; Tateishi, Hiroshi; Okamoto, Yoshinari; Inoue, Jun-ichiro; Fujita, Mikako; Otsuka, Masami
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2162
• Page End: 2167
• Publication Date: 2019-08-15
• Subjects: DTT dl-dithiothreitol -- IL-1α interleukin-1α -- MTT 3-(4, 5-dimethylthial-2-yl)-2, 5-diphenyltetrazalium bromide -- NF-κB nuclear factor-κB -- NpSH o-nitrobenzenethiol -- TRAF6 tumor necrosis factor receptor-associated factor 6; Zinc finger -- TRAF6 -- NF-κB -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.06.050
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Zinc fingers have rarely been regarded as drug targets. On the contrary, the zinc-binding site of enzymes has often been considered a target of inhibitors. We previously developed a dithiol compound called SN-1 that binds to the zinc finger protein tumor necrosis factor receptor-associated factor 6 (TRAF6) and suppresses downstream nuclear factor-κB (NF-κB) signaling. To determine the minimal structure requirements of TRAF6 inhibitors based on SN-1, NF-κB inhibitory activity and cytotoxicity of its derivatives including new compounds were examined. SN-2, an oxidative type of prodrug of SN-1 with 2-nitrophenylthio groups via disulfide, has the minimum structure for an inhibitor of TRAF6, as seen with cellular experiments. The importance of two side chains with a thiol group was shown with molecular modelling. This study may lead to development of selective TRAF6 inhibitors in the near future.