SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Damonte, Patrizia; Sociali, Giovanna; Parenti, Marco Daniele; Soncini, Debora; Bauer, Inga; Boero, Silvia; Grozio, Alessia; Holtey, Maria von; Piacente, Francesco; Becherini, Pamela; Sanguineti, Roberta; Salis, Annalisa; Damonte, Gianluca; Cea, Michele; Murone, Maximilien; Poggi, Alessandro; Nencioni, Alessio; Del Rio, Alberto; Bruzzone, Santina
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 20(2017)
• Page Start: 5849
• Page End: 5858
• Publication Date: 2017-10-15
• Subjects: SIRT6 sirtuin 6 -- TNF-α tumor necrosis factor -- PBMC peripheral blood mononuclear cell -- SEB staphylococcal enterotoxin B -- PMA phorbol-12-myristate-13-acetate -- 2-NBDG 2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino]-2-deoxy-d-glucose -- PDAC pancreatic ductal adenocarcinoma -- CFSE carboxyfluorescein succinimidyl ester; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.09.023
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: SIRT6 is an emerging drug target. Novel SIRT6 inhibitors with a salicylate-based structure have been identified. The new SIRT6 inhibitors sensitize pancreatic cancer cells to gemcitabine. The new SIRT6 inhibitors show anti-proliferative effects in T lymphocytes. Abstract: The NAD + -dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation. Notably, the new SIRT6 inhibitors effectively sensitize pancreatic cancer cells to gemcitabine. Finally, studies of compound fingerprinting and pharmacokinetics defined the drug-like properties of one of the new SIRT6 inhibitors, potentially allowing for subsequent in vivo proof-of-concept studies. In conclusion, new SIRT6 inhibitors with a salicylate-like structure were identified, which are active in cells and could potentially find applications in disease conditions, including cancer and immune-mediated disorders.