1597710-14-9Relevant academic research and scientific papers
Discovery of selective SIRT2 inhibitors as therapeutic agents in B-cell lymphoma and other malignancies
Chowdhury, Sarwat,Sripathy, Smitha,Webster, Alyssa,Park, Angela,Lao, Uyen,Hsu, Joanne H.,Loe, Taylor,Bedalov, Antonio,Simon, Julian A.
, (2020/02/11)
Genetic ablation as well as pharmacological inhibition of sirtuin 2 (SIRT2), an NAD+dependent protein deacylase, have therapeutic effects in various cancers and neurodegenerative diseases. Previously, we described the discovery of a dual SIRT1/SIRT2 inhibitor called cambinol (IC50 56 and 59 μM, respectively), which showed cytotoxic activity against cancer cells in vitro and a marked anti-proliferative effect in a Burkitt lymphoma mouse xenograft model. A number of recent studies have shown a protective effect of SIRT1 and SIRT3 in neurodegenerative and metabolic diseases as well as in certain cancers prompting us to initiate a medicinal chemistry effort to develop cambinol-based SIRT2-specific inhibitors devoid of SIRT1 or SIRT3 modulating activity. Here we describe potent cambinol-based SIRT2 inhibitors, several of which show potency of ~600 nM with >300 to >800-fold selectivity over SIRT1 and 3, respectively. In vitro, these inhibitors are found to be toxic to lymphoma and epithelial cancer cell lines. In particular, compounds 55 (IC50 SIRT2 0.25 μM and 25% inhibition at 50 μM against SIRT1 and SIRT3) and 56 (IC50 SIRT2 0.78 μM and 25% inhibition at 50 μM against SIRT1 and SIRT3) showed apoptotic as well as strong anti-proliferative properties against B-cell lymphoma cells.
Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors
Mahajan, Sumit S.,Scian, Michele,Sripathy, Smitha,Posakony, Jeff,Lao, Uyen,Loe, Taylor K.,Leko, Vid,Thalhofer, Angel,Schuler, Aaron D.,Bedalov, Antonio,Simon, Julian A.
, p. 3283 - 3294 (2014/05/20)
Sirtuins are a family of NAD+-dependent protein deacetylases that play critical roles in epigenetic regulation, stress responses, and cellular aging in eukaryotic cells. In an effort to identify small molecule inhibitors of sirtuins for potential use as chemotherapeutics as well as tools to modulate sirtuin activity, we previously identified a nonselective sirtuin inhibitor called cambinol (IC50 ≈ 50 μM for SIRT1 and SIRT2) with in vitro and in vivo antilymphoma activity. In the current study, we used saturation transfer difference (STD) NMR experiments with recombinant SIRT1 and 20 to map parts of the inhibitor that interacted with the protein. Our ongoing efforts to optimize cambinol analogues for potency and selectivity have resulted in the identification of isoform selective analogues: 17 with >7.8-fold selectivity for SIRT1, 24 with >15.4-fold selectivity for SIRT2, and 8 with 6.8- and 5.3-fold selectivity for SIRT3 versus SIRT1 and SIRT2, respectively. In vitro cytotoxicity studies with these compounds as well as EX527, a potent and selective SIRT1 inhibitor, suggest that antilymphoma activity of this compound class may be predominantly due to SIRT2 inhibition.
