Vedadi M, Arrowsmith CH (2008) Human HDAC7 harbors a class IIa histone deacetylasespecific zinc binding motif and cryptic deacetylase activity. J Biol Chem 283
(17):11355–11363. https://doi.org/10.1074/jbc.M707362200
21. Bressi JC, Jennings AJ, Skene R, Wu Y, Melkus R, De Jong R, O’Connell S, Grimshaw CE,
Navre M, Gangloff AR (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of
substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20(10):3142–3145.
https://doi.org/10.1016/j.bmcl.2010.03.091
22. Watson PJ, Fairall L, Santos GM, Schwabe JW (2012) Structure of HDAC3 bound to
co-repressor and inositol tetraphosphate. Nature 481(7381):335–340. https://doi.org/10.
1038/nature10728
23. Millard CJ, Watson PJ, Celardo I, Gordiyenko Y, Cowley SM, Robinson CV, Fairall L,
Schwabe JW (2013) Class I HDACs share a common mechanism of regulation by inositol
phosphates. Mol Cell 51(1):57–67. https://doi.org/10.1016/j.molcel.2013.05.020
24. Hai Y, Christianson DW (2016) Histone deacetylase 6 structure and molecular basis of
catalysis and inhibition. Nat Chem Biol 12(9):741–747. https://doi.org/10.1038/nchembio.
2134
25. Miyake Y, Keusch JJ, Wang L, Saito M, Hess D, Wang X, Melancon BJ, Helquist P, Gut H,
Matthias P (2016) Structural insights into HDAC6 tubulin deacetylation and its selective
inhibition. Nat Chem Biol 12(9):748–754. https://doi.org/10.1038/nchembio.2140
26. Hai Y, Shinsky SA, Porter NJ, Christianson DW (2017) Histone deacetylase 10 structure and
molecular function as a polyamine deacetylase. Nat Commun 8:15368. https://doi.org/10.
1038/ncomms15368
27. Zhang Y, Fang H, Jiao J, Xu W (2008) The structure and function of histone deacetylases: the
target for anti-cancer therapy. Curr Med Chem 15(27):2840–2849
28. Massa S, Mai A, Sbardella G, Esposito M, Ragno R, Loidl P, Brosch G (2001) 3-(4-aroyl-1Hpyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors. J Med Chem 44(13):2069–2072
29. Van Ommeslaeghe K, Elaut G, Brecx V, Papeleu P, Iterbeke K, Geerlings P, Tourwe D,
Rogiers V (2003) Amide analogues of TSA: synthesis, binding mode analysis and HDAC
inhibition. Bioorg Med Chem Lett 13(11):1861–1864
30. Wang DF, Wiest O, Helquist P, Lan-Hargest HY, Wiech NL (2004) On the function of the
14 A long internal cavity of histone deacetylase-like protein: implications for the design of
histone deacetylase inhibitors. J Med Chem 47(13):3409–3417. https://doi.org/10.1021/
jm0498497
31. Lu Q, Wang DS, Chen CS, Hu YD, Chen CS (2005) Structure-based optimization of
phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem 48(17):5530–5535.
https://doi.org/10.1021/jm0503749
32. Rodriquez M, Terracciano S, Cini E, Settembrini G, Bruno I, Bifulco G, Taddei M, GomezPaloma L (2006) Total synthesis, NMR solution structure, and binding model of the potent
histone deacetylase inhibitor FR235222. Angew Chem Int Ed Engl 45(3):423–427. https://doi.
org/10.1002/anie.200501995
33. Liu T, Kapustin G, Etzkorn FA (2007) Design and synthesis of a potent histone deacetylase
inhibitor. J Med Chem 50(9):2003–2006. https://doi.org/10.1021/jm061082q
34. Maulucci N, Chini MG, Micco SD, Izzo I, Cafaro E, Russo A, Gallinari P, Paolini C, Nardi
MC, Casapullo A, Riccio R, Bifulco G, Riccardis FD (2007) Molecular insights into
azumamide e histone deacetylases inhibitory activity. J Am Chem Soc 129(10):3007–3012.
https://doi.org/10.1021/ja0686256
35. Chen PC, Patil V, Guerrant W, Green P, Oyelere AK (2008) Synthesis and structure-activity
relationship of histone deacetylase (HDAC) inhibitors with triazole-linked cap group. Bioorg
Med Chem 16(9):4839–4853. https://doi.org/10.1016/j.bmc.2008.03.050
36. Di Micco S, Terracciano S, Bruno I, Rodriquez M, Riccio R, Taddei M, Bifulco G (2008)
Molecular modeling studies toward the structural optimization of new cyclopeptide-based
Structure-Based Design of Epigenetic Inhibitors
477
(17):11355–11363. https://doi.org/10.1074/jbc.M707362200
21. Bressi JC, Jennings AJ, Skene R, Wu Y, Melkus R, De Jong R, O’Connell S, Grimshaw CE,
Navre M, Gangloff AR (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of
substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20(10):3142–3145.
https://doi.org/10.1016/j.bmcl.2010.03.091
22. Watson PJ, Fairall L, Santos GM, Schwabe JW (2012) Structure of HDAC3 bound to
co-repressor and inositol tetraphosphate. Nature 481(7381):335–340. https://doi.org/10.
1038/nature10728
23. Millard CJ, Watson PJ, Celardo I, Gordiyenko Y, Cowley SM, Robinson CV, Fairall L,
Schwabe JW (2013) Class I HDACs share a common mechanism of regulation by inositol
phosphates. Mol Cell 51(1):57–67. https://doi.org/10.1016/j.molcel.2013.05.020
24. Hai Y, Christianson DW (2016) Histone deacetylase 6 structure and molecular basis of
catalysis and inhibition. Nat Chem Biol 12(9):741–747. https://doi.org/10.1038/nchembio.
2134
25. Miyake Y, Keusch JJ, Wang L, Saito M, Hess D, Wang X, Melancon BJ, Helquist P, Gut H,
Matthias P (2016) Structural insights into HDAC6 tubulin deacetylation and its selective
inhibition. Nat Chem Biol 12(9):748–754. https://doi.org/10.1038/nchembio.2140
26. Hai Y, Shinsky SA, Porter NJ, Christianson DW (2017) Histone deacetylase 10 structure and
molecular function as a polyamine deacetylase. Nat Commun 8:15368. https://doi.org/10.
1038/ncomms15368
27. Zhang Y, Fang H, Jiao J, Xu W (2008) The structure and function of histone deacetylases: the
target for anti-cancer therapy. Curr Med Chem 15(27):2840–2849
28. Massa S, Mai A, Sbardella G, Esposito M, Ragno R, Loidl P, Brosch G (2001) 3-(4-aroyl-1Hpyrrol-2-yl)-N-hydroxy-2-propenamides, a new class of synthetic histone deacetylase inhibitors. J Med Chem 44(13):2069–2072
29. Van Ommeslaeghe K, Elaut G, Brecx V, Papeleu P, Iterbeke K, Geerlings P, Tourwe D,
Rogiers V (2003) Amide analogues of TSA: synthesis, binding mode analysis and HDAC
inhibition. Bioorg Med Chem Lett 13(11):1861–1864
30. Wang DF, Wiest O, Helquist P, Lan-Hargest HY, Wiech NL (2004) On the function of the
14 A long internal cavity of histone deacetylase-like protein: implications for the design of
histone deacetylase inhibitors. J Med Chem 47(13):3409–3417. https://doi.org/10.1021/
jm0498497
31. Lu Q, Wang DS, Chen CS, Hu YD, Chen CS (2005) Structure-based optimization of
phenylbutyrate-derived histone deacetylase inhibitors. J Med Chem 48(17):5530–5535.
https://doi.org/10.1021/jm0503749
32. Rodriquez M, Terracciano S, Cini E, Settembrini G, Bruno I, Bifulco G, Taddei M, GomezPaloma L (2006) Total synthesis, NMR solution structure, and binding model of the potent
histone deacetylase inhibitor FR235222. Angew Chem Int Ed Engl 45(3):423–427. https://doi.
org/10.1002/anie.200501995
33. Liu T, Kapustin G, Etzkorn FA (2007) Design and synthesis of a potent histone deacetylase
inhibitor. J Med Chem 50(9):2003–2006. https://doi.org/10.1021/jm061082q
34. Maulucci N, Chini MG, Micco SD, Izzo I, Cafaro E, Russo A, Gallinari P, Paolini C, Nardi
MC, Casapullo A, Riccio R, Bifulco G, Riccardis FD (2007) Molecular insights into
azumamide e histone deacetylases inhibitory activity. J Am Chem Soc 129(10):3007–3012.
https://doi.org/10.1021/ja0686256
35. Chen PC, Patil V, Guerrant W, Green P, Oyelere AK (2008) Synthesis and structure-activity
relationship of histone deacetylase (HDAC) inhibitors with triazole-linked cap group. Bioorg
Med Chem 16(9):4839–4853. https://doi.org/10.1016/j.bmc.2008.03.050
36. Di Micco S, Terracciano S, Bruno I, Rodriquez M, Riccio R, Taddei M, Bifulco G (2008)
Molecular modeling studies toward the structural optimization of new cyclopeptide-based
Structure-Based Design of Epigenetic Inhibitors
477