SIRT6 inhibitors with salicylate-like structure show immunosuppressive and chemosensitizing effects

Patrizia Damonte, Giovanna Sociali, Marco Daniele Parenti, Debora Soncini, Inga Bauer, Silvia Boero, Alessia Grozio, Maria von Holtey, Francesco Piacente, Pamela Becherini, Roberta Sanguineti, Annalisa Salis, Gianluca Damonte, Michele Cea, Maximilien Murone, Alessandro Poggi, Alessio Nencioni, Alberto Del Rio, Santina Bruzzone

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.