123. Milite C, Feoli A, Viviano M, Rescigno D, Cianciulli A, Balzano AL, Mai A, Castellano S,
Sbardella G (2016) The emerging role of lysine methyltransferase SETD8 in human diseases.
Clin Epigenetics 8:102. https://doi.org/10.1186/s13148-016-0268-4
124. Reinberg D, Trojer P, Sbardella G (2007) Selective inhibitors for transferases. Google Patents
125. Valente S, Lepore I, Dell’Aversana C, Tardugno M, Castellano S, Sbardella G, Tomassi S, Di
Maro S, Novellino E, Di Santo R, Costi R, Altucci L, Mai A (2012) Identification of
PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells.
Biochimie 94(11):2308–2313. https://doi.org/10.1016/j.biochi.2012.06.003
126. Williams DE, Dalisay DS, Li F, Amphlett J, Maneerat W, Chavez MA, Wang YA,
Matainaho T, Yu W, Brown PJ, Arrowsmith CH, Vedadi M, Andersen RJ (2013)
Nahuoic acid A produced by a Streptomyces sp. isolated from a marine sediment is a selective
SAM-competitive inhibitor of the histone methyltransferase SETD8. Org Lett 15(2):414–417.
https://doi.org/10.1021/ol303416k
127. Williams DE, Izard F, Arnould S, Dalisay DS, Tantapakul C, Maneerat W, Matainaho T,
Julien E, Andersen RJ (2016) Structures of nahuoic acids B-E produced in culture by a
Streptomyces sp. isolated from a marine sediment and evidence for the inhibition of the
histone methyl transferase SETD8 in human cancer cells by nahuoic acid A. J Org Chem
81(4):1324–1332. https://doi.org/10.1021/acs.joc.5b02569
128. Ma A, Yu W, Li F, Bleich RM, Herold JM, Butler KV, Norris JL, Korboukh V, Tripathy A,
Janzen WP, Arrowsmith CH, Frye SV, Vedadi M, Brown PJ, Jin J (2014) Discovery of a
selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. J Med Chem
57(15):6822–6833. https://doi.org/10.1021/jm500871s
129. Ma A, Yu W, Xiong Y, Butler KV, Brown PJ, Jin J (2014) Structure-activity relationship
studies of SETD8 inhibitors. MedChemComm 5(12):1892–1898. https://doi.org/10.1039/
C4MD00317A
130. Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N,
Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ (2017)
Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for
p53 activation in high-risk neuroblastoma. Cancer Cell 31(1):50–63. https://doi.org/10.1016/j.
ccell.2016.12.002
131. Butler KV, Ma A, Yu W, Li F, Tempel W, Babault N, Pittella-Silva F, Shao J, Wang J, Luo M,
Vedadi M, Brown PJ, Arrowsmith CH, Jin J (2016) Structure-based design of a covalent
inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase. J Med
Chem 59(21):9881–9889. https://doi.org/10.1021/acs.jmedchem.6b01244
132. Blum G, Ibanez G, Rao X, Shum D, Radu C, Djaballah H, Rice JC, Luo M (2014) Smallmolecule inhibitors of SETD8 with cellular activity. ACS Chem Biol 9(11):2471–2478.
https://doi.org/10.1021/cb500515r
133. Judge RA, Zhu H, Upadhyay AK, Bodelle PM, Hutchins CW, Torrent M, Marin VL, Yu W,
Vedadi M, Li F, Brown PJ, Pappano WN, Sun C, Petros AM (2016) Turning a substrate
peptide into a potent inhibitor for the histone methyltransferase SETD8. ACS Med Chem Lett
7(12):1102–1106. https://doi.org/10.1021/acsmedchemlett.6b00303
134. Bromberg KD, Mitchell TR, Upadhyay AK, Jakob CG, Jhala MA, Comess KM, Lasko LM,
Li C, Tuzon CT, Dai Y, Li F, Eram MS, Nuber A, Soni NB, Manaves V, Algire MA, Sweis
RF, Torrent M, Schotta G, Sun C, Michaelides MR, Shoemaker AR, Arrowsmith CH, Brown
PJ, Santhakumar V, Martin A, Rice JC, Chiang GG, Vedadi M, Barsyte-Lovejoy D, Pappano
WN (2017) The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.
Nat Chem Biol 13(3):317–324. https://doi.org/10.1038/nchembio.2282
135. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T,
Haydon C, Ropero S, Petrie K, Iyer NG, Perez-Rosado A, Calvo E, Lopez JA, Cano A,
Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M
(2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common
hallmark of human cancer. Nat Genet 37(4):391–400. https://doi.org/10.1038/ng1531
Lysine Methyltransferases and Their Inhibitors
157
Sbardella G (2016) The emerging role of lysine methyltransferase SETD8 in human diseases.
Clin Epigenetics 8:102. https://doi.org/10.1186/s13148-016-0268-4
124. Reinberg D, Trojer P, Sbardella G (2007) Selective inhibitors for transferases. Google Patents
125. Valente S, Lepore I, Dell’Aversana C, Tardugno M, Castellano S, Sbardella G, Tomassi S, Di
Maro S, Novellino E, Di Santo R, Costi R, Altucci L, Mai A (2012) Identification of
PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells.
Biochimie 94(11):2308–2313. https://doi.org/10.1016/j.biochi.2012.06.003
126. Williams DE, Dalisay DS, Li F, Amphlett J, Maneerat W, Chavez MA, Wang YA,
Matainaho T, Yu W, Brown PJ, Arrowsmith CH, Vedadi M, Andersen RJ (2013)
Nahuoic acid A produced by a Streptomyces sp. isolated from a marine sediment is a selective
SAM-competitive inhibitor of the histone methyltransferase SETD8. Org Lett 15(2):414–417.
https://doi.org/10.1021/ol303416k
127. Williams DE, Izard F, Arnould S, Dalisay DS, Tantapakul C, Maneerat W, Matainaho T,
Julien E, Andersen RJ (2016) Structures of nahuoic acids B-E produced in culture by a
Streptomyces sp. isolated from a marine sediment and evidence for the inhibition of the
histone methyl transferase SETD8 in human cancer cells by nahuoic acid A. J Org Chem
81(4):1324–1332. https://doi.org/10.1021/acs.joc.5b02569
128. Ma A, Yu W, Li F, Bleich RM, Herold JM, Butler KV, Norris JL, Korboukh V, Tripathy A,
Janzen WP, Arrowsmith CH, Frye SV, Vedadi M, Brown PJ, Jin J (2014) Discovery of a
selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. J Med Chem
57(15):6822–6833. https://doi.org/10.1021/jm500871s
129. Ma A, Yu W, Xiong Y, Butler KV, Brown PJ, Jin J (2014) Structure-activity relationship
studies of SETD8 inhibitors. MedChemComm 5(12):1892–1898. https://doi.org/10.1039/
C4MD00317A
130. Veschi V, Liu Z, Voss TC, Ozbun L, Gryder B, Yan C, Hu Y, Ma A, Jin J, Mazur SJ, Lam N,
Souza BK, Giannini G, Hager GL, Arrowsmith CH, Khan J, Appella E, Thiele CJ (2017)
Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for
p53 activation in high-risk neuroblastoma. Cancer Cell 31(1):50–63. https://doi.org/10.1016/j.
ccell.2016.12.002
131. Butler KV, Ma A, Yu W, Li F, Tempel W, Babault N, Pittella-Silva F, Shao J, Wang J, Luo M,
Vedadi M, Brown PJ, Arrowsmith CH, Jin J (2016) Structure-based design of a covalent
inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase. J Med
Chem 59(21):9881–9889. https://doi.org/10.1021/acs.jmedchem.6b01244
132. Blum G, Ibanez G, Rao X, Shum D, Radu C, Djaballah H, Rice JC, Luo M (2014) Smallmolecule inhibitors of SETD8 with cellular activity. ACS Chem Biol 9(11):2471–2478.
https://doi.org/10.1021/cb500515r
133. Judge RA, Zhu H, Upadhyay AK, Bodelle PM, Hutchins CW, Torrent M, Marin VL, Yu W,
Vedadi M, Li F, Brown PJ, Pappano WN, Sun C, Petros AM (2016) Turning a substrate
peptide into a potent inhibitor for the histone methyltransferase SETD8. ACS Med Chem Lett
7(12):1102–1106. https://doi.org/10.1021/acsmedchemlett.6b00303
134. Bromberg KD, Mitchell TR, Upadhyay AK, Jakob CG, Jhala MA, Comess KM, Lasko LM,
Li C, Tuzon CT, Dai Y, Li F, Eram MS, Nuber A, Soni NB, Manaves V, Algire MA, Sweis
RF, Torrent M, Schotta G, Sun C, Michaelides MR, Shoemaker AR, Arrowsmith CH, Brown
PJ, Santhakumar V, Martin A, Rice JC, Chiang GG, Vedadi M, Barsyte-Lovejoy D, Pappano
WN (2017) The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.
Nat Chem Biol 13(3):317–324. https://doi.org/10.1038/nchembio.2282
135. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T,
Haydon C, Ropero S, Petrie K, Iyer NG, Perez-Rosado A, Calvo E, Lopez JA, Cano A,
Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M
(2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common
hallmark of human cancer. Nat Genet 37(4):391–400. https://doi.org/10.1038/ng1531
Lysine Methyltransferases and Their Inhibitors
157