Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

• DOI: 10.1016/j.ejmech.2015.08.024
• Publication Date: 2015-08-14T17:50:13Z
• Authors: Giovanna Sociali; Lauretta Galeno; Marco Daniele Par...; Alessia Grozio; Inga Bauer; Mario Passalacqua; Silvia Boero; Alessandra Donadini; Enrico Millo; Marta Bellotti; Laura Sturla; Patrizia Damonte; Alessandra Puddu; Claudia Ferroni; Greta Varchi; Claudio Franceschi; Alberto Ballestrero; Alessandro Poggi; Santina Bruzzone; Alessio Nencioni; Alberto Del Rio
• Keywords: Small molecule inhibitors; Cell Survival; Quinazolinedione; NAD-dependent deacetylases; Anticancer drugs; Piperazines; Structure-Activity Relationship; 03 medical and health sciences; Anticancer drugs; Chemotherapy; Molecular design; NAD-dependent deacetylases; Quinazolinedione; Sirtuins; Small molecule inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology; Antineoplastic Combined Chemotherapy Protocols; Tumor Cells, Cultured; Chemotherapy; Humans; Sirtuins; Enzyme Inhibitors; Quinazolinones; 0303 health sciences; Molecular design; Cell Death; Dose-Response Relationship, Drug; Molecular Structure; 3. Good health; Phthalazines; Drug Screening Assays, Antitumor; DNA Damage

The NAD(+)-dependent sirtuin SIRT6 is highly expressed in human breast, prostate, and skin cancer where it mediates resistance to cytotoxic agents and prevents differentiation. Thus, SIRT6 is an attractive target for the development of new anticancer agents to be used alone or in combination with chemo- or radiotherapy. Here we report on the identification of novel quinazolinedione compounds with inhibitory activity on SIRT6. As predicted based on SIRT6's biological functions, the identified new SIRT6 inhibitors increase histone H3 lysine 9 acetylation, reduce TNF-α production and increase glucose uptake in cultured cells. In addition, these compounds exacerbate DNA damage and cell death in response to the PARP inhibitor olaparib in BRCA2-deficient Capan-1 cells and cooperate with gemcitabine to the killing of pancreatic cancer cells. In conclusion, new SIRT6 inhibitors with a quinazolinedione-based structure have been identified which are active in cells and could potentially find applications in cancer treatment.