A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.Show MeSH
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Mentions: Comparison of the structures of the MDM2–p53 and MDMX–p53 complexes (Kussie et al, 1996; Popowicz et al, 2007) revealed that the N-terminal hydrophobic pocket of MDMX for p53 binding is much shallower than that of MDM2. This information explained why MDM2 inhibitors failed to affect MDMX–p53 binding and also prompted us to initiate a computational structure-based screening using the AutoDock computer program (Morris et al, 2008) for the docking of virtual compounds that could distinguish the p53 binding sites on MDM2 and MDMX. From our initial computational screening of half a million of commercially available compounds from the ChemDiv chemical library, we selected and purchased 50 top candidates. These compounds were tested in cell-based assays at 10 µM for their ability to induce p53 levels in human lung carcinoma H460 cells using an immunoblotting (IB) analyses. To our delight, one small molecule, 10-[2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)butanoyl]-10H-phenothiazine (abbreviated as INZ; Fig 1B), induced p53 levels as effectively as actinomycin D (ActD; 10 nM) and in a much more pronounced manner than did the rest of the compounds tested (Fig 1A and data not shown).
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.