3,734
Views
26
CrossRef citations to date
0
Altmetric
Review Article

Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat)

, &
Pages 1124-1136 | Received 17 Feb 2020, Accepted 12 Apr 2020, Published online: 05 May 2020

References

  • Jing H, Lin H. Sirtuins in epigenetic regulation. Chem Rev 2015;115:2350–75.
  • Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007;450:712–6.
  • Han J, Hubbard BP, Lee J, et al. Analysis of 41 cancer cell lines reveals excessive allelic loss and novel mutations in the SIRT1 gene. Cell Cycle 2013;12:263–70.
  • Kim D, Nguyen DM, Dobbin MM, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 2007;26:3169–79.
  • Westphal CH, Dipp MA, Guarente L. A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 2007;32:555–60.
  • Hubbard BP, Gomes AP, Dai H, et al. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013;339:1216–9.
  • Lin Z, Fang D. The roles of SIRT1 in cancer. Genes Cancer 2013;4:97–104.
  • Rifaï K, Idrissou M, Penault-Llorca F, et al. Breaking down the contradictory roles of histone deacetylase SIRT1 in human breast cancer. Cancers 2018;10:409.
  • Herranz D, Serrano M. Sirt1: recent lessons from mouse models. Nat Rev Cancer 2010;10:819–23.
  • Fujita Y, Yamashita T. Sirtuins in neuroendocrine regulation and neurological diseases. Front Neurosci 2018;12:778.
  • Blum CA, Ellis JL, Loh C, et al. SIRT1 modulation as a novel approach to the treatment of diseases of aging. J Med Chem 2011;54:417–32.
  • Hu J, Jing H, Lin H. Sirtuin inhibitors as anticancer agents. Future Med Chem 2014;6:945–66.
  • Kozako T, Suzuki T, Yoshimitsu M, et al. Anticancer agents targeted to sirtuins. Molecules 2014;19:20295–313.
  • Kumar A, Chauhan S. How much successful are the medicinal chemists in modulation of SIRT1: a critical review. Eur J Med Chem 2016;119:45–69.
  • Napper AD, Hixon J, McDonagh T, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 2005;48:8045–54.
  • Solomon JM, Pasupuleti R, Xu L, et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol 2006;26:28–38.
  • Huhtiniemi T, Suuronen T, Rinne VM, et al. Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 Inhibitors. J Med Chem 2008;51:4377–80.
  • Liu Y, Gerber R, Wu J, et al. High-throughput assays for sirtuin enzymes: a microfluidic mobility shift assay and a bioluminescence assay. Anal Biochem 2008;378:53–9.
  • Smith BC, Hallows WC, Denu JM. A continuous microplate assay for sirtuins and nicotinamide-producing enzymes. Anal Biochem 2009;394:101–9.
  • Peck B, Chen CY, Ho KK, et al. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther 2010;9:844–55.
  • Pasco MY, Rotili D, Altucci L, et al. Characterization of sirtuin inhibitors in nematodes expressing a muscular dystrophy protein reveals muscle cell and behavioral protection by specific sirtinol analogues. J Med Chem 2010;53:1407–11.
  • Rotili D, Tarantino D, Carafa V, et al. Identification of tri- and tetracyclic pyrimidinediones as sirtuin inhibitors. ChemMedChem 2010;5:674–7.
  • Mellini P, Carafa V, Di Rienzo B, et al. Carprofen analogues as sirtuin inhibitors: enzyme and cellular studies. ChemMedChem 2012;7:1905–8.
  • Disch JS, Evindar G, Chiu CH, et al. Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3. J Med Chem 2013;56:3666–79.
  • Gertz M, Fischer F, Nguyen GTT, et al. Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc Natl Acad Sci USA 2013;110:E2772–81.
  • Kokkonen P, Rahnasto-Rilla M, Mellini P, et al. Studying SIRT6 regulation using H3K56 based substrate and small molecules. Eur J Pharm Sci 2014;63:71–6.
  • Yang T, Chen X, Jin H-X, et al. Functionalized tetrahydro-1H-pyrido[4,3-b]indoles: a novel chemotype with Sirtuin 2 inhibitory activity. Eur J Med Chem 2015;92:145–55.
  • Therrien E, Larouche G, Nguyen N, et al. Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors. Bioorg Med Chem Lett 2015;25:2514–8.
  • Ekblad T, Schüler H. Sirtuins are unaffected by PARP inhibitors containing planar nicotinamide bioisosteres. Chem Biol Drug Des 2016;87:478–82.
  • Schnekenburger M, Goffin E, Lee J-Y, et al. Discovery and characterization of R/S-N-3-cyanophenyl-N′-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea, a new histone deacetylase class III inhibitor exerting antiproliferative activity against cancer cell lines. J Med Chem 2017;60:4714–33.
  • Zhao X, Allison D, Condon B, et al. The 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition. J Med Chem 2013;56:963–9.
  • Nayagam VM, Wang X, Cheng Tan Y, et al. SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J Biomol Screen 2006;11:959–67.
  • Hubbard BP, Loh C, Gomes AP, et al. Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. Cell Cycle 2013;12:2233–40.
  • Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008;451:583–6.
  • Zhao W, Kruse J-P, Tang Y, et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 2008;451:587–90.
  • Gueguen C, Palmier B, Plotkine M, et al. Neurological and histological consequences induced by in vivo cerebral oxidative stress: evidence for beneficial effects of SRT1720, a sirtuin 1 activator, and sirtuin 1-mediated neuroprotective effects of poly(ADP-ribose) polymerase inhibition. PLoS One 2014;9:e87367.
  • Westerberg G, Chiesa JA, Andersen CA, et al. Safety, pharmacokinetics, pharmacogenomics and QT concentration − effect modelling of the SirT1 inhibitor selisistat in healthy volunteers. Br J Clin Pharmacol 2015;79:477–91.
  • Sauve AA, Wolberger C, Schramm VL, Boeke JB. The biochemistry of sirtuins. Annu Rev Biochem 2006;75:435–65.
  • Stein RL, Kinetics of enzyme action. New York, NY: Wiley; 2011.
  • Kabra N, Li Z, Chen L, et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem 2009;284:18210–7.
  • Cea M, Soncini D, Fruscione F, et al. Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells. PLoS One 2011;6:e22739.
  • Zhu H, Xia L, Zhang Y, et al. Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression. PLoS One 2012;7:e31431.
  • Rotili D, Tarantino D, Nebbioso A, et al. Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells. J Med Chem 2012;55:10937–47.
  • Suzuki T, Khan MNA, Sawada H, et al. Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors. J Med Chem 2012;55:5760–73.
  • Lugrin J, Ciarlo E, Santos A, et al. The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock. Biochim Biophys Acta 2013;1833:1498–510.
  • Schuster S, Penke M, Gorski T, et al. Resveratrol differentially regulates NAMPT and SIRT1 in hepatocarcinoma cells and primary human hepatocytes. PLoS One 2014;9:e91045.
  • Smith MR, Syed A, Lukacsovich T, et al. A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet 2014;23:2995–3007.
  • Valle C, Salvatori I, Gerbino V, et al. Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways. Cell Death Dis 2014;5:e1296–e1296.
  • Li Y, Wang K, Feng Y, et al. Novel role of silent information regulator 1 in acute endothelial cell oxidative stress injury. Biochim Biophys Acta 2014;1842:2246–56.
  • Zhang JG, Hong DF, Zhang CW, et al. Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress. Cancer Sci 2014;105:445–54.
  • Gollavilli PN, Kanugula AK, Koyyada R, et al. AMPK inhibits MTDH expression via GSK3b and SIRT1 activation: potential role in triple negative breast cancer cell proliferation. FEBS Journal 2015; 282:3971–85.
  • Kim HB, Lee SH, Um JH, et al. Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition. Int J Biol Sci 2015;11:923–34.
  • Kim HB, Lee SH, Um JH, et al. Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1. Oncotarget 2015;6:36202–18.
  • Hu Y, Zhang N, Fan Q, et al. Protective efficacy of carnosic acid against hydrogen peroxide induced oxidative injury in HepG2 cells through the SIRT1 pathway. Can J Physiol Pharmacol 2015;93:1–7.
  • Asaka R, Miyamoto T, Yamada Y, et al. Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target. Lab Investig 2015;95:1363–73.
  • Kumari S, Chaurasia SN, Nayak MK, et al. Sirtuin inhibition induces apoptosis-like changes in platelets and thrombocytopenia. J Biol Chem 2015;290:12290–9.
  • Lim HW, Kang SG, Ryu JK, et al. SIRT1 deacetylates RORgt and enhances Th17 cell generation. J Exp Med 2015;212:607–17.
  • Kim HW, Kim SA, Ahn SG. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncol Rep 2016;35:235–42.
  • Kim BS, Lee CH, Chang GE, et al. A potent and selective small molecule inhibitor of sirtuin 1 promotes differentiation of pluripotent P19 cells into functional neurons. Sci Rep 2016;6:34324.
  • Chen G, Zhang B, Xu H, et al. Suppression of Sirt1 sensitizes lung cancer cells to WEE1 inhibitor MK-1775-induced DNA damage and apoptosis. Oncogene 2017;36:6863–10.
  • Yang X, Wei J, He Y, et al. SIRT1 inhibition promotes atherosclerosis through impaired autophagy. Oncotarget 2017;8:51447–61.
  • Sun J, Guo E, Yang J, et al. Carbon monoxide ameliorates hepatic ischemia/reperfusion injury via sirtuin 1-mediated deacetylation of high-mobility group box 1 in rats. Liver Transplant 2017;23:510–26.
  • Ceballos MP, Decándido G, Quiroga AD, et al. Inhibition of sirtuins 1 and 2 impairs cell survival and migration and modulates the expression of P-glycoprotein and MRP3 in hepatocellular carcinoma cell lines. Toxicol Lett 2018;289:63–74.
  • Jiang H, Xin S, Yan Y, et al. Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms. Atherosclerosis 2018;271:182–92.
  • Shokri Afra H, Zangooei M, Meshkani R, et al. Is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells. J Physiol Biochem 2019;75:125–33.
  • Yan S, Miao L, Lu Y, Wang L. Sirtuin 1 inhibits TNF-α-mediated osteoclastogenesis of bone marrow-derived macrophages through both ROS generation and TRPV1 activation. Mol Cell Biochem 2019;455:135–45.
  • Huang X, Sun J, Chen G, et al. Z. Resveratrol promotes diabetic wound healing via SIRT1-FOXO1-c-Myc signaling pathway-mediated angiogenesis. Front Pharmacol 2019;10:1–10.
  • Zhang Y, Li Y, Li J, et al. SIRT1 alleviates isoniazid-induced hepatocyte injury by reducing histone acetylation in the IL-6 promoter region. Int Immunopharmacol 2019;67:348–55.
  • Daenthanasanmak A, Iamsawat S, Chakraborty P, et al. Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice. Blood 2019;133:266–79.
  • Wang Y, Zeng J, Wu W, et al. Nicotinamide N-methyltransferase enhances chemoresistance in breast cancer through SIRT1 protein stabilization. Breast Cancer Res 2019;21:17.
  • Qin T, Liu W, Huo J, et al. SIRT1 expression regulates the transformation of resistant esophageal cancer cells via the epithelial-mesenchymal transition. Biomed Pharmacother 2018;103:308–16.
  • Mvunta DH, Miyamoto T, Asaka R, et al. SIRT1 regulates the chemoresistance and invasiveness of ovarian carcinoma cells. Transl Oncol 2017;10:621–31.
  • Süssmuth SD, Darpo B, Westerberg G. et al. An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s disease. Br J Clin Pharmacol 2015;79:465–76.
  • Beier UH, Wang L, Bhatti TR, et al. Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 2011;31:1022–9.
  • Kwon HS, Lim HW, Wu J, et al. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J Immunol 2012;188:2712–21.
  • Zhao L, An R, Yang Y, et al. Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: the role of SIRT1 signaling. J Pineal Res 2015;59:230–9.
  • Oon CE, Strell C, Yeong KY, et al. SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo. Eur J Pharmacol 2015;757:59–67.
  • Kim HD, Hesterman J, Call T, et al. SIRT1 mediates depression-like behaviors in the nucleus accumbens. J Neurosci 2016;36:8441–52.
  • Guo YJ, Dong SY, Cui XX, et al. Resveratrol alleviates MPTP-induced motor impairments and pathological changes by autophagic degradation of a-synuclein via SIRT1-deacetylated LC3. Mol Nutr Food Res 2016;60:2161–75.
  • Huang J, Tian R, Yang Y, et al. The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia. Innate Immun 2017;23:678–86.
  • Çakir I, Perello M, Lansari O, et al. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS One 2009;4:e8322.
  • Velásquez DA, Martínez G, Romero A, et al. The central sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 2011;60:1177–85.
  • Qi LS, Yao L, Liu W, et al. Sirtuin type 1 mediates the retinal protective effect of hydrogen-rich saline against light-induced damage in rats. Invest Ophthalmol Vis Sci 2015;56:8268–79.
  • Ugwu FN, Yu AP, Sin TK, et al. Protective effect of unacylated ghrelin on compression-induced skeletal muscle injury mediated by SIRT1-signaling. Front Physiol 2017;8:962.
  • Nikseresht S, Khodagholi F, Ahmadiani A. Protective effects of ex‐527 on cerebral ischemia–reperfusion injury through necroptosis signaling pathway attenuation. J Cell Physiol 2019;234:1816–26.
  • Yu LM, Dong X, Xue XD, et al. Protection of the myocardium against ischemia/reperfusion injury by punicalagin through an SIRT1-NRF-2-HO-1-dependent mechanism. Chem Biol Interact 2019;306:152–62.
  • Yu L, Sun Y, Cheng L, et al. Melatonin receptor-mediated protection against myocardial ischemia/reperfusion injury: role of SIRT1. J Pineal Res 2014;57:228–38.
  • Yang Y, Jiang S, Dong Y, et al. Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res 2015;58:61–70.
  • Peng Z, Zhang W, Qiao J, He B. Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD. Int Immunopharmacol 2018;62:23–8.
  • Yu L, Li S, Tang X, et al. Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats: role of SIRT1 activation. Apoptosis 2017;22:942–54.
  • Yao X, Chen W, Liu J, et al. Deep vein thrombosis is modulated by inflammation regulated via sirtuin 1/NF-κB signalling pathway in a rat model. Thromb Haemost 2019;119:421–30.
  • Yoo A, Narayan VP, Hong EY, et al. Scopolin ameliorates high-fat diet induced hepatic steatosis in mice: potential involvement of SIRT1-mediated signaling cascades in the liver. Sci Rep 2017;7:2251.
  • Zhang D, Qiu X, Li J, et al. MiR-23a-3p-regulated abnormal acetylation of FOXP3 induces regulatory T cell function defect in Graves disease. Biol Chem 2019;400:639–50.