Aller GS, Machutta CA, Diaz E, Jiang Y, Johnson NW, Knight SD, Kruger RG, McCabe MT,
Dhanak D, Tummino PJ, Creasy CL, Miller WH (2012) Identification of potent, selective, cellactive inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett 3(12):
1091–1096. https://doi.org/10.1021/ml3003346
47. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y, Gu J, Ardayfio O,
Zhang JH, Yan X, Fang J, Mi Y, Zhang M, Zhou T, Feng G, Chen Z, Li G, Yang T, Zhao K,
Liu X, Yu Z, Lu CX, Atadja P, Li E (2012) Selective inhibition of Ezh2 by a small molecule
inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A 109(52):21360–21365.
https://doi.org/10.1073/pnas.1210371110
48. Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP,
Kuznetsova E, Rougie M, Jiang A, Pattenden SG, Norris JL, James LI, Roth BL, Brown PJ,
Frye SV, Arrowsmith CH, Hahn KM, Wang GG, Vedadi M, Jin J (2013) An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol 8(6):
1324–1334. https://doi.org/10.1021/cb400133j
49. Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, Allison DF, Cai L, Rockowitz S,
Liu S, Liu Y, Li F, Vedadi M, Frye SV, Garcia BA, Zheng D, Jin J, Wang GG (2015) Selective
inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses
MLL-rearranged leukemia. Blood 125(2):346–357. https://doi.org/10.1182/blood-2014-06581082
50. Nasveschuk CG, Gagnon A, Garapaty-Rao S, Balasubramanian S, Campbell R, Lee C,
Zhao F, Bergeron L, Cummings R, Trojer P, Audia JE, Albrecht BK, Harmange JC (2014)
Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS
Med Chem Lett 5(4):378–383. https://doi.org/10.1021/ml400494b
51. Gehling VS, Vaswani RG, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F,
Good AC, Campbell R, Lee C, Dakin LA, Cook AS, Gagnon A, Harmange JC, Audia JE,
Cummings RT, Normant E, Trojer P, Albrecht BK (2015) Discovery, design, and synthesis of
indole-based EZH2 inhibitors. Bioorg Med Chem Lett 25(17):3644–3649. https://doi.org/10.
1016/j.bmcl.2015.06.056
52. Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P,
Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT,
Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N,
1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med Chem
59(21):9928–9941. https://doi.org/10.1021/acs.jmedchem.6b01315
53. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M,
Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM, Kuntz KW, Keilhack H
(2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 110(19):7922–7927. https://doi.
org/10.1073/pnas.1303800110
54. Morera L, Lubbert M, Jung M (2016) Targeting histone methyltransferases and demethylases
in clinical trials for cancer therapy. Clin Epigenetics 8:57. https://doi.org/10.1186/s13148-0160223-4
55. Ribrag V, Soria J-C, Michot J-M, Schmitt A, Postel-Vinay S, Bijou F, Thomson B,
Keilhack H, Blakemore SJ, Reyderman L (2015) Phase 1 study of tazemetostat (EPZ-6438),
an inhibitor of enhancer of zeste-homolog 2 (EZH2): preliminary safety and activity in
relapsed or refractory non-Hodgkin lymphoma (NHL) patients. Blood 126(23):473–473
56. Clinical Trials. www.clinicaltrials.gov. Accessed 26 Jan 2018
57. Lu B, Shen X, Zhang L, Liu D, Zhang C, Cao J, Shen R, Zhang J, Wang D, Wan H, Xu Z, Ho
M-H, Zhang M, Zhang L, He F, Tao W (2018) Discovery of EBI-2511: a highly potent and
orally active EZH2 inhibitor for the treatment of non-Hodgkin’s lymphoma. ACS Med Chem
Lett 9(2):98–102. https://doi.org/10.1021/acsmedchemlett.7b00437
Lysine Methyltransferases and Their Inhibitors
151
Dhanak D, Tummino PJ, Creasy CL, Miller WH (2012) Identification of potent, selective, cellactive inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett 3(12):
1091–1096. https://doi.org/10.1021/ml3003346
47. Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y, Gu J, Ardayfio O,
Zhang JH, Yan X, Fang J, Mi Y, Zhang M, Zhou T, Feng G, Chen Z, Li G, Yang T, Zhao K,
Liu X, Yu Z, Lu CX, Atadja P, Li E (2012) Selective inhibition of Ezh2 by a small molecule
inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A 109(52):21360–21365.
https://doi.org/10.1073/pnas.1210371110
48. Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, Liu F, Gao C, Huang XP,
Kuznetsova E, Rougie M, Jiang A, Pattenden SG, Norris JL, James LI, Roth BL, Brown PJ,
Frye SV, Arrowsmith CH, Hahn KM, Wang GG, Vedadi M, Jin J (2013) An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol 8(6):
1324–1334. https://doi.org/10.1021/cb400133j
49. Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, Allison DF, Cai L, Rockowitz S,
Liu S, Liu Y, Li F, Vedadi M, Frye SV, Garcia BA, Zheng D, Jin J, Wang GG (2015) Selective
inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses
MLL-rearranged leukemia. Blood 125(2):346–357. https://doi.org/10.1182/blood-2014-06581082
50. Nasveschuk CG, Gagnon A, Garapaty-Rao S, Balasubramanian S, Campbell R, Lee C,
Zhao F, Bergeron L, Cummings R, Trojer P, Audia JE, Albrecht BK, Harmange JC (2014)
Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS
Med Chem Lett 5(4):378–383. https://doi.org/10.1021/ml400494b
51. Gehling VS, Vaswani RG, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F,
Good AC, Campbell R, Lee C, Dakin LA, Cook AS, Gagnon A, Harmange JC, Audia JE,
Cummings RT, Normant E, Trojer P, Albrecht BK (2015) Discovery, design, and synthesis of
indole-based EZH2 inhibitors. Bioorg Med Chem Lett 25(17):3644–3649. https://doi.org/10.
1016/j.bmcl.2015.06.056
52. Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P,
Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT,
Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N,
1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med Chem
59(21):9928–9941. https://doi.org/10.1021/acs.jmedchem.6b01315
53. Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M,
Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM, Kuntz KW, Keilhack H
(2013) Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A 110(19):7922–7927. https://doi.
org/10.1073/pnas.1303800110
54. Morera L, Lubbert M, Jung M (2016) Targeting histone methyltransferases and demethylases
in clinical trials for cancer therapy. Clin Epigenetics 8:57. https://doi.org/10.1186/s13148-0160223-4
55. Ribrag V, Soria J-C, Michot J-M, Schmitt A, Postel-Vinay S, Bijou F, Thomson B,
Keilhack H, Blakemore SJ, Reyderman L (2015) Phase 1 study of tazemetostat (EPZ-6438),
an inhibitor of enhancer of zeste-homolog 2 (EZH2): preliminary safety and activity in
relapsed or refractory non-Hodgkin lymphoma (NHL) patients. Blood 126(23):473–473
56. Clinical Trials. www.clinicaltrials.gov. Accessed 26 Jan 2018
57. Lu B, Shen X, Zhang L, Liu D, Zhang C, Cao J, Shen R, Zhang J, Wang D, Wan H, Xu Z, Ho
M-H, Zhang M, Zhang L, He F, Tao W (2018) Discovery of EBI-2511: a highly potent and
orally active EZH2 inhibitor for the treatment of non-Hodgkin’s lymphoma. ACS Med Chem
Lett 9(2):98–102. https://doi.org/10.1021/acsmedchemlett.7b00437
Lysine Methyltransferases and Their Inhibitors
151