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Naturally occurring small molecule compounds that target histone deacetylases and their potential applications in cancer therapy

Abstract

Epigenetics is defined as the heritable alteration of gene expression without change to the DNA sequence. Epigenetic abnormalities play a role in various diseases, including cancer. Epigenetic regulation of gene expression occurs through histone chemical modifications and DNA methylation. Lysine acetylation is one of the major histone chemical modifications essential for epigenetic gene expression. Histone acetylation is reversibly regulated by histone acetyltransferases and histone deacetylases, which are molecular targets for cancer therapy. There has been an explosion of research in epigenetic-related drug discovery, and accordingly many small molecule compounds have been developed. Notably, several small molecule inhibitors of histone deacetylases have been approved for the treatment of cancer. This review will introduce natural products, their derivative inhibitors of histone deacetylases, and their clinical development.

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References

  1. 1.

    Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11:726–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther. 2009;8:1409–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Turner BM. Histone acetylation and an epigenetic code. BioEssays. 2000;22:836–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod. 2016;79:629–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K. A new antifungal antibiotic, trichostatin. J Antibiot. 1976;29:1–6.

    CAS  Article  Google Scholar 

  7. 7.

    Yoshida M, Nomura S, Beppu T. Effects of trichostatins on differentiation of murine erythroleukemia cells. Cancer Res. 1987;47:3688–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265:17174–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Yang X-J, Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol. 2008;9:206–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Wang C, Yang W, Dong F, Guo Y, Tan J, Ruan S, et al. The prognostic role of Sirt1 expression in solid malignancies: a meta-analysis. Oncotarget. 2017;8:66343–51.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Wilking MJ, Ahmad N. The role of SIRT1 in Cancer. Am J Pathol. 2015;185:26–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Kim H-S, Vassilopoulos A, Wang R-H, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 2011;20:487–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Yang MH, Laurent G, Bause AS, Spang R, German N, Haigis MC, et al. HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS. Mol Cancer Res. 2013;11:1072–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Zhou W, Ni TK, Wronski A, Glass B, Skibinski A, Beck A, et al. The SIRT2 deacetylase stabilizes slug to control malignancy of basal-like breast cancer. Cell Rep. 2016;17:1302–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Candido E. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978;14:105–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Bruni J, Wilder BJ. Valproic acid: review of a new antiepileptic drug. Arch Neurol. 1979;36:393–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78.

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Tassara M, Döhner K, Brossart P, Held G, Götze K, Horst H-A, et al. Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood. 2014;123:4027–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Avallone A, Piccirillo MC, Delrio P, Pecori B, Di Gennaro E, Aloj L, et al. Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid-short Radiotherapy-rectum 3rd trial). BMC Cancer. 2014;14:875 https://doi.org/10.1186/1471-2407-14-875

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bilen MA, Fu S, Falchook GS, Ng CS, Wheler JJ, Abdelrahim M, et al. Phase I trial of valproic acid and lenalidomide in patients with advanced cancer. Cancer Chemother Pharmacol. 2015;75:869–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, et al. A phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int J Radiat Oncol Biol Phys. 2015;92:986–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Caponigro F, Di Gennaro E, Ionna F, Longo F, Aversa C, Pavone E, et al. Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial. BMC Cancer. 2016;16:918 https://doi.org/10.1186/s12885-016-2957-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Avallone A, Piccirillo MC, Di Gennaro E, Romano C, Calabrese F, Roca MS, et al. Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol. Ther Adv Med Oncol. 2020;12:1758835920929589 https://doi.org/10.1177/1758835920929589

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Park HK, Han BR, Park WH. Combination of arsenic trioxide and valproic acid efficiently inhibits growth of lung cancer cells via G2/M-phase arrest and apoptotic cell death. Int J Mol Sci. 2020;21:2649 https://doi.org/10.3390/ijms21072649

    CAS  Article  PubMed Central  Google Scholar 

  26. 26.

    Su JM-F, Murray JC, McNall‐Knapp RY, Bowers DC, Shah S, Adesina AM, et al. A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma. Pediatr Blood Cancer. 2020;67:e28283 https://doi.org/10.1002/pbc.28283

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Gore SD, Weng L-J, Figg WD, Zhai S, Donehower RC, Dover G, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2002;8:963–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Nudelman A, Ruse M, Aviram A, Rabizadeh E, Shaklai M, Zimrah Y, et al. Novel anticancer prodrugs of butyric acid. 2. J Med Chem. 1992;35:687–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Yoshida M, Beppu T. Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A. Exp Cell Res. 1988;177:122–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999;401:188–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Mori H, Urano Y, Abe F, Furukawa S, Furukawa S, Tsurumi Y, et al. FR235222, a fungal metabolite, is a novel immunosuppressant that inhibits mammalian histone deacetylase (HDAC). I. Taxonomy, fermentation, isolation and biological activities. J Antibiot. 2003;56:72–9.

    CAS  Article  Google Scholar 

  32. 32.

    Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, et al. A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA. 1998;95:3003–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Marks PA. Discovery and development of SAHA as an anticancer agent. Oncogene. 2007;26:1351–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Campbell P, Thomas CM. Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. 2016. J Oncol Pharm Pract. 2017;23:143–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Laubach JP, Moreau P, San-Miguel JF, Richardson PG. Panobinostat for the management of multiple myeloma. Clin Cancer Res. 2015;21:4767–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, et al. Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem. 1999;42:3001–3.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA.1999;96:4592–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, et al. MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res. 2002;62:6108–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Connolly RM, Li H, Jankowitz RC, Zhang Z, Rudek MA, Jeter SC, et al. Combination epigenetic therapy in advanced breast cancer with 5-Azacitidine and Entinostat: A Phase II national cancer institute/stand up to cancer study. Clin Cancer Res. 2017;23:2691–701.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Choy E, Ballman K, Chen J, Dickson MA, Chugh R, George S, et al. SARC018_SPORE02: Phase II study of mocetinostat administered with gemcitabine for patients with metastatic leiomyosarcoma with progression or relapse following prior treatment with gemcitabine-containing therapy. Sarcoma. 2018;2068517. https://doi.org/10.1155/2018/2068517

  41. 41.

    Itazaki H, Nagashima K, Sugita K, Yoshida H, Kawamura Y, Yasuda Y, et al. Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J Antibiot. 1990;43:1524–32.

    CAS  Article  Google Scholar 

  42. 42.

    Taunton J, Hassig CA, Schreiber SL. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science. 1996;272:408–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D, et al. In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J. 2002;21:6820–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Komatsu Y, Tomizaki K, Tsukamoto M, Kato T, Nishino N, Sato S, et al. Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res. 2001;61:4459–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, et al. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA. 1996;93:13143–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Schepper SD, Bruwiere H, Verhulst T, Steller U, Andries L, Wouters W, et al. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degradation of survivin. J Pharm Exp Ther. 2003;304:881–8.

    Article  CAS  Google Scholar 

  47. 47.

    Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res. 1998;241:126–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Furumai R, Matsuyama A, Kobashi N, Lee K-H, Nishiyama M, Nakajima H, et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 2002;62:4916–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW. Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J Am Chem Soc. 2011;133:12474–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Khan O, La Thangue NB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 2012;90:85–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Masuoka Y, Nagai A, Shin-ya K, Furihata K, Nagai K, Suzuki K, et al. Spiruchostatins A and B, novel gene expression-enhancing substances produced by Pseudomonas sp. Tetrahedron Lett. 2001;42:41–4.

    CAS  Article  Google Scholar 

  52. 52.

    Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T, Sakai T. A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol. 2013;43:1080–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Kim D, Lee IS, Jung JH, Yang SI, Psammaplin A. a natural bromotyrosine derivative from a sponge, possesses the antibacterial activity against methicillin-resistant Staphylococcus aureus and the DNA gyrase-inhibitory activity. Arch Pharm Res. 1999;22:25–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Kim D, Lee IS, Jung JH, Lee CO, Choi SU, Psammaplin A. a natural phenolic compound, has inhibitory effect on human topoisomerase II and is cytotoxic to cancer cells. Anticancer Res. 1999;19:4085–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Piña IC, Gautschi JT, Wang G-Y-S, Sanders ML, Schmitz FJ, France D, et al. Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J Org Chem. 2003;68:3866–73.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  56. 56.

    Baud MGJ, Leiser T, Petrucci V, Gunaratnam M, Neidle S, Meyer-Almes F-J, et al. Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors. Beilstein J Org Chem. 2013;9:81–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Druesne N, Pagniez A, Mayeur C, Thomas M, Cherbuy C, Duée P-H, et al. Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis. 2004;25:1227–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Jo HJ, Song JD, Kim KM, Cho YH, Kim KH, Park YC. Diallyl disulfide induces reversible G2/M phase arrest on a p53-independent mechanism in human colon cancer HCT-116 cells. Oncol Rep. 2008;19:275–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Taori K, Paul VJ, Luesch H. Structure and Activity of Largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium symploca sp. J Am Chem Soc. 2008;130:1806–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Salvador LA, Park H, Al-Awadhi FH, Liu Y, Kim B, Zeller SL, et al. Modulation of activity profiles for largazole-based HDAC inhibitors through alteration of prodrug properties. ACS Med Chem Lett. 2014;5:905–10.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Landry J, Slama JT, Sternglanz R. Role of NAD+ in the deacetylase activity of the SIR2-like proteins. Biochem Biophys Res Commun. 2000;278:685–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Wall KA, Klis M, Kornet J, Coyle D, Amé J-C, Jacobson MK, et al. Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues. Biochem J. 1998;335:631–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM. Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem. 2003;278:50985–98.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem. 2002;277:45099–107.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by sir2α promotes cell survival under stress. Cell. 2001;107:137–48.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci USA. 2002;99:13653–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003;11:437–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Denu JM. Linking chromatin function with metabolic networks: Sir2 family of NAD+-dependent deacetylases. Trends Biochem Sci. 2003;28:41–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373:1618–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Hoogsteen IJ, Pop LAM, Marres HAM, Merkx MAW, van den Hoogen FJA, van der Kogel AJ, et al. Oxygen-modifying treatment with ARCON reduces the prognostic significance of hemoglobin in squamous cell carcinoma of the head and neck. Int J Radiat Oncol. 2006;64:83–9.

    CAS  Article  Google Scholar 

  71. 71.

    Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol. 2012;30:1777–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Janssens GO, Langendijk JA, Terhaard CH, Doornaert PA, van den Ende P, de Jong MA, et al. Quality-of-life after radiotherapy for advanced laryngeal cancer: Results of a phase III trial of the Dutch Head and Neck Society. Radiother Oncol. 2016;119:213–20.

    PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Hoskin PJ, Rojas AM, Bentzen SM, Saunders MI. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol. 2010;28:4912–8.

    PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem. 2001;276:38837–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA. Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci USA. 2001;98:15113–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006;66:4368–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Napper AD, Hixon J, McDonagh T, Keavey K, Pons J-F, Barker J, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem. 2005;48:8045–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Gertz M, Fischer F, Nguyen GTT, Lakshminarasimhan M, Schutkowski M, Weyand M, et al. Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc Natl Acad Sci USA. 2013;110:E2772–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Solomon JM, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano PS, 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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Yasuda M, Wilson DR, Fugmann SD, Moaddel R. Synthesis and characterization of SIRT6 protein coated magnetic beads: identification of a novel inhibitor of SIRT6 deacetylase from medicinal plant extracts. Anal Chem. 2011;83:7400–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Singh N, Ravichandran S, Spelman K, Fugmann SD, Moaddel R. The identification of a novel SIRT6 modulator from Trigonella foenum-graecum using ligand fishing with protein coated magnetic beads. J Chromatogr B Anal Technol Biomed Life Sci. 2014;0:105–11.

    Article  CAS  Google Scholar 

  82. 82.

    Heger V, Tyni J, Hunyadi A, Horáková L, Lahtela-Kakkonen M, Rahnasto-Rilla M. Quercetin based derivatives as sirtuin inhibitors. Biomed Pharmacother. 2019;111:1326–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Yuan Z, Chen L, Fan L, Tang M, Yang G, Yang H, et al. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin Cancer Res. 2006;12:3193–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    An F, Wang S, Tian Q, Zhu D. Effects of orientin and vitexin from Trollius chinensis on the growth and apoptosis of esophageal cancer EC-109 cells. Oncol Lett. 2015;10:2627–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Lall RK, Adhami VM, Mukhtar H. Dietary flavonoid fisetin for cancer prevention and treatment. Mol Nutr Food Res. 2016;60:1396–405.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Lee C-Y, Chien Y-S, Chiu T-H, Huang W-W, Lu C-C, Chiang J-H, et al. Apoptosis triggered by vitexin in U937 human leukemia cells via a mitochondrial signaling pathway. Oncol Rep. 2012;28:1883–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Singh IP, Milligan KE, Gerwick WH. Tanikolide, a toxic and antifungal lactone from the marine cyanobacterium Lyngbya majuscula. J Nat Prod. 1999;62:1333–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Gutiérrez M, Andrianasolo EH, Shin WK, Goeger DE, Yokochi A, Schemies J, et al. Structural and synthetic investigations of tanikolide dimer, a SIRT2 selective inhibitor, and tanikolide seco-acid from the Madagascar marine cyanobacterium Lyngbya majuscula. J Org Chem. 2009;74:5267–75.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Kudo N, Ito A, Arata M, Nakata A, Yoshida M. Identification of a novel small molecule that inhibits deacetylase but not defatty-acylase reaction catalysed by SIRT2. Philos Trans R Soc B Biol Sci. 2018;373:20170070 https://doi.org/10.1098/rstb.2017.0070

    CAS  Article  Google Scholar 

  90. 90.

    Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, et al. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun. 2015;6:6263 https://doi.org/10.1038/ncomms7263

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Feldman JL, Dittenhafer-Reed KE, Kudo N, Thelen JN, Ito A, Yoshida M, et al. Kinetic and structural basis for acyl-group selectivity and NAD+ dependence in sirtuin-catalyzed deacylation. Biochemistry. 2015;54:3037–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Y.M. wrote the initial manuscript. Y.M., Y.S. and R.K. designed the figures. A.I. wrote and edited the manuscript.

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Correspondence to Akihiro Ito.

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Maemoto, Y., Shimizu, Y., Katoh, R. et al. Naturally occurring small molecule compounds that target histone deacetylases and their potential applications in cancer therapy. J Antibiot 74, 667–676 (2021). https://doi.org/10.1038/s41429-021-00459-6

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