Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Recent Progress on the Discovery of Sirt2 Inhibitors for the Treatment of Various Cancers

Author(s): Ting Wang, Zhuyu Xu, Yongping Lu, Jianyou Shi, Wenbo Liu, Chengchen Zhang, Zhongliang Jiang, Baowen Qi* and Lan Bai*

Volume 19, Issue 12, 2019

Page: [1051 - 1058] Pages: 8

DOI: 10.2174/1568026619666190510103416

Price: $65

Abstract

Sirtuins family is a class of NDA+ dependent protein deacetylases that play a key role in the regulation of several aspects of biological processes, such as cell cycle regulation, autophagy, immune and inflammatory response. Many studies have shown that sirtuins2 as a key player in the cancer pathway is of great significance in tumorigenesis. This review summarizes the newly discovered, in recent years, some SIRT2 inhibitors for cancer target structure, action mechanism, biological activity, substrate specificity, and signaling pathways.

Keywords: Sirtuins, Sirt2 inhibitor, Substrate, Signaling pathways, Cancer, N-terminal.

« Previous Next »
Graphical Abstract

[1]
Wolffe, A.; Matzke, M. Epigenetics: Regulation through repression. Science, 1999, 286(5439), 481-486. [http:// dx.doi.org/10.11226/science.286.5439.481]. [PMID: 10521337].
[2]
Chaturvedi, P.; Tyagi, S.C. Epigenetic mechanisms underlying cardiac degeneration and regeneration. Int. J. Cardiol., 2014, 173(1), 1-11. [http://dx.doi.org/10.1016/j.ijcard.2014.02.008]. [PMID: 24636549].
[3]
Chalkiadaki, A.; Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer, 2015, 15(10), 608-624. [http://dx.doi.org/10.1038/nrc3985]. [PMID: 26383140].
[4]
Shuang, S.; Zeming, L.U.; Jin, J.J.; Yong, C. Genetic modes of epigenetic modification and its research progress. Chin. Sci. Bull., 2016, 61(36), 3878-3886. [http://dx.doi.org/10.1360/N972016-00972].
[5]
Chalkiadaki, A.; Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol., 2012, 8(5), 287-296. [http://dx.doi.org/10.1038/nrendo.2011.225]. [PMID: 22249520].
[6]
Chang, H.C.; Guarente, L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol. Metab., 2014, 25(3), 138-145. [http://dx.doi.org/10.1016/j.tem.2013.12.001]. [PMID: 24388149].
[7]
Inoue, T.; Hiratsuka, M.; Osaki, M.; Yamada, H.; Kishimoto, I.; Yamaguchi, S.; Nakano, S.; Katoh, M.; Ito, H.; Oshimura, M. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene, 2007, 26(7), 945-957. [http://dx.doi.org/10.1038/sj.onc.1209857]. [PMID: 16909107].
[8]
Xiaobo, M. Design, Synthesis and Activity of A Novel Selective Epigenetic Target SIRT2 Inhibitor; Xihua University: Chengdu, 2017.
[9]
Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5(9), 769-784. [http://dx.doi.org/10.1038/nrd2133]. [PMID: 16955068].
[10]
Haigis, M.C.; Sinclair, D.A. Mammalian sirtuins: Biological insights and disease relevance. Annu. Rev. Pathol., 2010, 5, 253-295. [http://dx.doi.org/10.1146/annurev.pathol.4.110807.092250]. [PMID: 20078221].
[11]
Michan, S.; Sinclair, D. Sirtuins in mammals: Insights into their biological function. Biochem. J., 2007, 404(1), 1-13. [http://dx.doi.org/10.1042/BJ20070140]. [PMID: 17447894].
[12]
Moniot, S.; Weyand, M.; Steegborn, C. Structures, substrates, and regulators of Mammalian sirtuins - opportunities and challenges for drug development. Front. Pharmacol., 2012, 3(3), 16. [http://dx.doi.org/10.3389/fphar.2012.00016]. [PMID: 22363286].
[13]
Chopra, V.; Quinti, L.; Kim, J.; Vollor, L.; Narayanan, K.L.; Edgerly, C.; Cipicchio, P.M.; Lauver, M.A.; Choi, S.H.; Silverman, R.B.; Ferrante, R.J.; Hersch, S.; Kazantsev, A.G. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models. Cell Rep., 2012, 2(6), 1492-1497. [http://dx.doi.org/10.1016/j.celrep.2012.11.001]. [PMID: 23200855].
[14]
Gomes, P.; Fleming Outeiro, T.; Cavadas, C. Emerging Role of Sirtuin 2 in the regulation of mammalian metabolism. Trends Pharmacol. Sci., 2015, 36(11), 756-768. [http://dx.doi.org/10.1016/j.tips.2015.08.001]. [PMID: 26538315].
[15]
Liu, G.; Park, S.H.; Imbesi, M.; Nathan, W.J.; Zou, X.; Zhu, Y.; Jiang, H.; Parisiadou, L.; Gius, D. Loss of NAD-dependent protein deacetylase sirtuin-2 alters mitochondrial protein acetylation and dysregulates mitophagy. Antioxid. Redox Signal., 2017, 26(15), 849-863. [http://dx.doi.org/10.1089/ars.2016.6662]. [PMID: 27460777].
[16]
Kozako, T.; Suzuki, T.; Yoshimitsu, M.; Arima, N.; Honda, S.; Soeda, S. Anticancer agents targeted to sirtuins. Molecules, 2014, 19(12), 20295-20313. [http://dx.doi.org/10.3390/molecules191220295]. [PMID: 25486244].
[17]
Wang, F.; Nguyen, M.; Qin, F.X.; Tong, Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell, 2007, 6(4), 505-504. [http://dx.doi.org/10.1111/j.1474-9726.2007.00304.x].
[18]
Kim, H.S.; Vassilopoulos, A.; Wang, R.H.; Lahusen, T.; Xiao, Z.; Xu, X.; Li, C.; Veenstra, T.D.; Li, B.; Yu, H.; Ji, J.; Wang, X.W.; Park, S.H.; Cha, Y.I.; Gius, D.; Deng, C.X. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell, 2011, 20(4), 487-499. [http://dx.doi.org/10.1016/j.ccr.2011.09.004]. [PMID: 22014574].
[19]
Maxwell, M.M.; Tomkinson, E.M.; Nobles, J.; Wizeman, J.W.; Amore, A.M.; Quinti, L.; Chopra, V.; Hersch, S.M.; Kazantsev, A.G. The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. Hum. Mol. Genet., 2011, 20(20), 3986-3996. [http://dx.doi.org/10.1093/hmg/ddr326]. [PMID: 21791548].
[20]
Hu, F.; Sun, X.; Li, G.; Wu, Q.; Chen, Y.; Yang, X.; Luo, X.; Hu, J.; Wang, G. Inhibition of SIRT2 limits tumour angiogenesis via inactivation of the STAT3/VEGFA signalling pathway. Cell Death Dis., 2018, 10(1), 9. [http://dx.doi.org/10.1038/s41419-018-1260-z]. [PMID: 30584257].
[21]
Huang, S.; Zhao, Z.; Tang, D.; Zhou, Q.; Li, Y.; Zhou, L.; Yin, Y.; Wang, Y.; Pan, Y.; Dorfman, R.G.; Ling, T.; Zhang, M. Downregulation of sirt2 inhibits invasion of hepatocellular carcinoma by inhibiting energy metabolism. Transl. Oncol., 2017, 10(6), 917-927. [http://dx.doi.org/10.1016/j.tranon.2017.09.006]. [PMID: 28992545].
[22]
Kim, H.S.; Vassilopoulos, A.; Wang, R.H.; Lahusen, T.; Xiao, Z.; Xu, X.; Li, C.; Veenstra, T.D.; Li, B.; Yu, H.; Ji, J.; Wang, X.W.; Park, S.H.; Cha, Y.I.; Gius, D.; Deng, C.X. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell, 2011, 20(4), 487-499. [http://dx.doi.org/10.1016/j.ccr.2011.09.004]. [PMID: 22014574].
[23]
McGlynn, L.M.; Zino, S.; MacDonald, A.I.; Curle, J.; Reilly, J.E.; Mohammed, Z.M.A.; McMillan, D.C.; Mallon, E.; Payne, A.P.; Edwards, J.; Shiels, P.G. SIRT2: Tumour suppressor or tumour promoter in operable breast cancer? Eur. J. Cancer, 2014, 50(2), 290-301. [http://dx.doi.org/10.1016/j.ejca.2013.10.005]. [PMID: 24183459].
[24]
Soung, Y.H.; Pruitt, K.; Chung, J. Epigenetic silencing of ARRDC3 expression in basal-like breast cancer cells. Sci. Rep., 2014, 4(19)(Suppl.), 3846. [PMID: 24457910].
[25]
Cheon, M.G.; Kim, W.; Choi, M.; Kim, J.E. AK-1, A specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells. Cancer Lett., 2015, 356(2 Pt B), 637-645. [http://dx.doi.org/10.1016/j.canlet.2014.10.012]. [PMID: 25312940].
[26]
Yan-Hua, D.U.; Zhang, H.Y.; Sun, H.; Amp, O. Reduced expression of SIRT2 in serous ovarian carcinoma promotes cell proliferation,migration and invasion. Chinese J. Pathophysiol., 2015, 11(10), 1181-1189.
[27]
Jing, H.; Hu, J.; He, B.; Negrón Abril, Y.L.; Stupinski, J.; Weiser, K.; Carbonaro, M.; Chiang, Y.L.; Southard, T.; Giannakakou, P.; Weiss, R.S.; Lin, H.A. SIRT2-selective inhibitor promotes c-myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell, 2016, 29(3), 297-310. [http://dx.doi.org/10.1016/j.ccell.2016.02.007]. [PMID: 26977881].
[28]
Singh, S.; Kumar, P.U.; Thakur, S.; Kiran, S.; Sen, B.; Sharma, S.; Rao, V.V.; Poongothai, A.R.; Ramakrishna, G. Expression/locali-zation patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells. Tumour Biol., 2015, 36(8), 6159-6171. [http://dx.doi.org/10.1007/s13277-015-3300-y]. [PMID: 25794641].
[29]
Kim, H.W.; Kim, S.A.; Ahn, S.G. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncol. Rep., 2016, 35(1), 235-242. [http://dx.doi.org/10.3892/or.2015.4381]. [PMID: 26530275].
[30]
He, X.; Nie, H.; Hong, Y.; Sheng, C.; Xia, W.; Ying, W. SIRT2 activity is required for the survival of C6 glioma cells. Biochem. Biophys. Res. Commun., 2012, 417(1), 468-472. [http://dx.doi.org/10.1016/j.bbrc.2011.11.141]. [PMID: 22166219].
[31]
Grbesa, I.; Pajares, M.J.; Martínez-Terroba, E.; Agorreta, J.; Mikecin, A.M.; Larráyoz, M.; Idoate, M.A.; Gall-Troselj, K.; Pio, R.; Montuenga, L.M. Expression of sirtuin 1 and 2 is associated with poor prognosis in non-small cell lung cancer patients. PLoS One, 2015, 10(4)e0124670 [http://dx.doi.org/10.1371/journal.pone.0124670]. [PMID: 25915617].
[32]
Dryden, S.C.; Nahhas, F.A.; Nowak, J.E.; Goustin, A.S.; Tainsky, M.A. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell. Biol., 2003, 23(9), 3173-3185. [http://dx.doi.org/10.1128/MCB.23.9.3173-3185.2003]. [PMID: 12697818].
[33]
Seo, K.S.; Park, J.H.; Heo, J.Y.; Jing, K.; Han, J.; Min, K.N.; Kim, C.; Koh, G.Y.; Lim, K.; Kang, G.Y.; Uee Lee, J.; Yim, Y.H.; Shong, M.; Kwak, T.H.; Kweon, G.R. SIRT2 regulates tumour hypoxia response by promoting HIF-1α hydroxylation. Oncogene, 2015, 34(11), 1354-1362. [http://dx.doi.org/10.1038/onc.2014.76]. [PMID: 24681946].
[34]
Suematsu, T.; Li, Y.; Kojima, H.; Nakajima, K.; Oshimura, M.; Inoue, T. Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effects on BubR1 degradation during the prometaphase/anaphase transition. Biochem. Biophys. Res. Commun., 2014, 453(3), 588-594. [http://dx.doi.org/10.1016/j.bbrc.2014.09.128]. [PMID: 25285631].
[35]
Hong, N.; Feng, Y.; Jing-Wen, T.; Tong-De, T.; Hua-Hua, L.I.; Guang-Xing, Y.; Yi-Xiao, F.; Hao-Ben, Z. Influences of SIRT2 silence on proliferation, migration and invasion of gastric cancer SGC-7901 cells. Chinese Med. Biotechnol., 2018, 13(6), 526-531.
[36]
Rumpf, T.; Schiedel, M.; Karaman, B.; Roessler, C.; North, B.J.; Lehotzky, A.; Oláh, J.; Ladwein, K.I.; Schmidtkunz, K.; Gajer, M.; Pannek, M.; Steegborn, C.; Sinclair, D.A.; Gerhardt, S.; Ovádi, J.; Schutkowski, M.; Sippl, W.; Einsle, O.; Jung, M. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat. Commun., 2015, 6(2382), 6263. [http://dx.doi.org/10.1038/ncomms7263]. [PMID: 25672491].
[37]
Jing, H.; Zhang, X.; Wisner, S.A.; Chen, X.; Spiegelman, N.A.; Linder, M.E.; Lin, H. SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a. eLife, 2017, 6, 32. [http://dx.doi.org/10.7554/eLife.32436]. [PMID: 29239724].
[38]
Du, J.; Zhou, Y.; Su, X.; Yu, J.J.; Khan, S.; Jiang, H.; Kim, J.; Woo, J.; Kim, J.H.; Choi, B.H.; He, B.; Chen, W.; Zhang, S.; Cerione, R.A.; Auwerx, J.; Hao, Q.; Lin, H. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science, 2011, 334(6057), 806-809. [http://dx.doi.org/10.1126/science.1207861]. [PMID: 22076378].
[39]
Mathias, R.A.; Greco, T.M.; Oberstein, A.; Budayeva, H.G.; Chakrabarti, R.; Rowland, E.A.; Kang, Y.; Shenk, T.; Cristea, I.M. Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell, 2014, 159(7), 1615-1625. [http://dx.doi.org/10.1016/j.cell.2014.11.046]. [PMID: 25525879].
[40]
Tan, M.; Peng, C.; Anderson, K.A.; Chhoy, P.; Xie, Z.; Dai, L.; Park, J.; Chen, Y.; Huang, H.; Zhang, Y.; Ro, J.; Wagner, G.R.; Green, M.F.; Madsen, A.S.; Schmiesing, J.; Peterson, B.S.; Xu, G.; Ilkayeva, O.R.; Muehlbauer, M.J.; Braulke, T.; Mühlhausen, C.; Backos, D.S.; Olsen, C.A.; McGuire, P.J.; Pletcher, S.D.; Lombard, D.B.; Hirschey, M.D.; Zhao, Y. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab., 2014, 19(4), 605-617. [http://dx.doi.org/10.1016/j.cmet.2014.03.014]. [PMID: 24703693].
[41]
Hoffmann, G.; Breitenbücher, F.; Schuler, M.; Ehrenhofer-Murray, A.E. A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer. J. Biol. Chem., 2014, 289(8), 5208-5216. [http://dx.doi.org/10.1074/jbc.M113.487736]. [PMID: 24379401].
[42]
Ma, W.; Zhao, X.; Wang, K.; Liu, J.; Huang, G. Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer. Cancer Biol. Ther., 2018, 19(9), 835-846. [http://dx.doi.org/10.1080/15384047.2018.1480281]. [PMID: 30067423].
[43]
Zhao, D.; Mo, Y.; Li, M.T.; Zou, S.W.; Cheng, Z.L.; Sun, Y.P.; Xiong, Y.; Guan, K.L.; Lei, Q.Y. NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J. Clin. Invest., 2014, 124(12), 5453-5465. [http://dx.doi.org/10.1172/JCI76611]. [PMID: 25384215].
[44]
Faubert, B.; Boily, G.; Izreig, S.; Griss, T.; Samborska, B.; Dong, Z.; Dupuy, F.; Chambers, C.; Fuerth, B.J.; Viollet, B.; Mamer, O.A.; Avizonis, D.; DeBerardinis, R.J.; Siegel, P.M.; Jones, R.G. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab., 2013, 17(1), 113-124. [http://dx.doi.org/10.1016/j.cmet.2012.12.001]. [PMID: 23274086].
[45]
Mungai, P.T.; Waypa, G.B.; Jairaman, A.; Prakriya, M.; Dokic, D.; Ball, M.K.; Schumacker, P.T. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol. Cell. Biol., 2011, 31(17), 3531-3545. [http://dx.doi.org/10.1128/MCB.05124-11]. [PMID: 21670147].
[46]
Jones, R.G.; Plas, D.R.; Kubek, S.; Buzzai, M.; Mu, J.; Xu, Y.; Birnbaum, M.J.; Thompson, C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell, 2005, 18(3), 283-293. [http://dx.doi.org/10.1016/j.molcel.2005.03.027]. [PMID: 15866171].

Rights & Permissions Print Cite
Article Metrics
74
8
1
© 2024 Bentham Science Publishers | Privacy Policy