Identification of a Selective SIRT2 Inhibitor and Its Anti-breast Cancer Activity

Abstract

SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro. The compound increased the acetylation level of eukaryotic translation initiation factor 5A (eIF5A), a physiological substrate of SIRT2, and reduced cell viability of human breast cancer cells accompanied with a decrease in c-Myc expression. These results suggest that the compound is cellular effective and has potential for development as a therapeutic agent against breast cancers by specific inhibition of SIRT2.Key words SIRT2; c-Myc; breast cancer; high-throughput screening; eukaryotic translation initiation factor 5ASirtuins are a family of nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylases shown to play biological and physiological roles in diverse cellular processes such as metabolism, transcription, and DNA repair. Mammals have seven sirtuins that display different subcellular localizations and functions. SIRT2 is a predominantly cytosolic protein and was originally reported as a microtubule deacetylase, 1) but further studies have revealed that SIRT2 acts as a deacetylase for histones and a number of non-histone proteins. This wide variety of substrates might be correlated with physiological roles of SIRT2 in diverse biological processes such as the cell cycle, autophagy, and energy metabolism. 2)Many studies suggest an important involvement of SIRT2 in neurodegeneration, inflammation, bacterial infection, and cancer, and that modulation of SIRT2 activity could be novel strategy for therapies against these disorders.3-5) However, pharmacological evidence for SIRT2 as a valid therapeutic target has not yet been shown. Therefore, potent and selective SIRT2 inhibitors are required for initial proof of concept studies. Although there are several reports describing SIRT2 inhibitors to date, 6) specificity and cellular potency of most present SIRT2 inhibitors appear to be insufficient for elucidating in vivo SIRT2 functions. In this regard, development of potent and highly specific SIRT2 inhibitors has been recently achieved. 7,8) Here, we identified a potent and specific SIRT2 inhibitor by high-throughput screening. Because the fundamental structure of the compound is different from that of existing SIRT2 inhibitors, it may serve as a novel class of chemical tool for exploring SIRT2 functions in cells.

SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

“…Thus SIRT2 may provide an additional link between K-Ras4a signaling and cellular metabolism. Given that Ras proteins play critical roles in many human cancers, SIRT2, as a Ras regulator, may be an important therapeutic target for cancer, which is consistent with several recent reports ( Jing et al, 2016 ; Moniot et al, 2017 ; Shah et al, 2016 ; Wang et al, 2014 ; Wilking-Busch et al, 2017 ; Xu et al, 2016 ; Zhao et al, 2013 , 2016 ). The physiological and pathophysiological roles of SIRT2 thus merit further investigation.…”

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

“…Sirt2 has been discussed as an anticancer target but also tumor suppressive activities of Sirt2 have been mentioned (8)(9)(10)(11)(12)(13)(14)(15). These effects might be tissue or organ specific which complicates drug development and no Sirt2 inhibitor has reached clinical trials yet.…”

Novel small molecule SIRT2 inhibitors induce cell death in leukemic cell lines

“…2 , 3 , 4 , 5 and 6 ). Selective SIRT2 inhibitors induce cell death in non-small cell lung cancer and breast cancer cell lines [ 41 , 42 ]. Thus, SIRT2 inhibitors are promising lead candidates for use in cancer treatments.…”