Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities

SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.CA164245 - NCI NIH HHS; R01 CA101992 - NCI NIH HHS; R21 CA129046 - NCI NIH HHS; R21 CA141036 - NCI NIH HHS; P50 GM067041 - NIGMS NIH HHS; UL1RR025771 - NCRR NIH HHS; CA101992 - NCI NIH HHS; UL1 RR025771 - NCRR NIH HHS; GM-073855 - NIGMS NIH HHS; CA129046 - NCI NIH HHS; R21 CA164245 - NCI NIH HHS; GM-067041 - NIGMS NIH HHS; CA141036 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HH

Identification of a novel polyprenylated acylphloroglucinol-derived SIRT1 inhibitor with cancer-specific anti-proliferative and invasion-suppressing activities

SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.CA164245 - NCI NIH HHS; R01 CA101992 - NCI NIH HHS; R21 CA129046 - NCI NIH HHS; R21 CA141036 - NCI NIH HHS; P50 GM067041 - NIGMS NIH HHS; UL1RR025771 - NCRR NIH HHS; CA101992 - NCI NIH HHS; UL1 RR025771 - NCRR NIH HHS; GM-073855 - NIGMS NIH HHS; CA129046 - NCI NIH HHS; R21 CA164245 - NCI NIH HHS; GM-067041 - NIGMS NIH HHS; CA141036 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HH