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98. Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S,
Kuznetsova E, Smil D, Barsyte-Lovejoy D, Li F, Poda G, Schapira M, Wu H, Dong A,
Senisterra G, Stukalov A, Huber KVM, Schonegger A, Marcellus R, Bilban M, Bock C,
Brown PJ, Zuber J, Bennett KL, Al-Awar R, Delwel R, Nerlov C, Arrowsmith CH, SupertiFurga G (2015) Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha
N-terminal leukemia. Nat Chem Biol 11(8):571–578. https://doi.org/10.1038/nchembio.1859
99. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D,
Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL (2015)
Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature
525(7568):206–211. https://doi.org/10.1038/nature15251
100. Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T,
Wang J, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL,
Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J (2015) Pharmacologic
inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
Cancer Cell 27(4):589–602. https://doi.org/10.1016/j.ccell.2015.02.016
101. Zhou JX, Dhawan S, Fu H, Snyder E, Bottino R, Kundu S, Kim SK, Bhushan A (2013)
Combined modulation of polycomb and trithorax genes rejuvenates beta cell replication. J Clin
Invest 123(11):4849–4858. https://doi.org/10.1172/JCI69468
102. He S, Senter TJ, Pollock J, Han C, Upadhyay SK, Purohit T, Gogliotti RD, Lindsley CW,
Cierpicki T, Stauffer SR, Grembecka J (2014) High-affinity small-molecule inhibitors of the
menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein
interaction. J Med Chem 57(4):1543–1556. https://doi.org/10.1021/jm401868d
103. Keating ST, El-Osta A (2013) Transcriptional regulation by the Set7 lysine methyltransferase.
Epigenetics 8(4):361–372. https://doi.org/10.4161/epi.24234
104. Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA,
Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S,
Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS,
Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME,
Owen DR, Zaph C, Vedadi M, Arrowsmith CH (2014) (R)-PFI-2 is a potent and selective
inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci U S A 111(35):
12853–12858. https://doi.org/10.1073/pnas.1407358111
105. Niu Y, Shi D, Li L, Guo J, Liu H, Yao X (2017) Revealing inhibition difference between PFI-2
enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis. Sci Rep 7:46547. https://doi.org/10.1038/srep46547
106. Francis NJ, Rowlands M, Workman P, Jones K, Aherne W (2012) Small-molecule inhibitors
of the protein methyltransferase SET7/9 identified in a high-throughput screen. J Biomol
Screen 17(8):1102–1109. https://doi.org/10.1177/1087057112452137
107. Mori S, Iwase K, Iwanami N, Tanaka Y, Kagechika H, Hirano T (2010) Development of novel
bisubstrate-type inhibitors of histone methyltransferase SET7/9. Bioorg Med Chem 18(23):
8158–8166. https://doi.org/10.1016/j.bmc.2010.10.022
108. Meng F, Cheng S, Ding H, Liu S, Liu Y, Zhu K, Chen S, Lu J, Xie Y, Li L, Liu R, Shi Z,
Zhou Y, Liu YC, Zheng M, Jiang H, Lu W, Liu H, Luo C (2015) Discovery and optimization
of novel, selective histone methyltransferase SET7 inhibitors by pharmacophore- and dockingbased virtual screening. J Med Chem 58(20):8166–8181. https://doi.org/10.1021/acs.
jmedchem.5b01154
109. Takemoto Y, Ito A, Niwa H, Okamura M, Fujiwara T, Hirano T, Handa N, Umehara T,
Sonoda T, Ogawa K, Tariq M, Nishino N, Dan S, Kagechika H, Yamori T, Yokoyama S,
Yoshida M (2016) Identification of cyproheptadine as an inhibitor of SET domain containing
lysine methyltransferase 7/9 (Set7/9) that regulates estrogen-dependent transcription. J Med
Chem 59(8):3650–3660. https://doi.org/10.1021/acs.jmedchem.5b01732
Lysine Methyltransferases and Their Inhibitors
155
Chem 60(12):4818–4839. https://doi.org/10.1021/acs.jmedchem.6b01796
98. Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S,
Kuznetsova E, Smil D, Barsyte-Lovejoy D, Li F, Poda G, Schapira M, Wu H, Dong A,
Senisterra G, Stukalov A, Huber KVM, Schonegger A, Marcellus R, Bilban M, Bock C,
Brown PJ, Zuber J, Bennett KL, Al-Awar R, Delwel R, Nerlov C, Arrowsmith CH, SupertiFurga G (2015) Pharmacological targeting of the Wdr5-MLL interaction in C/EBPalpha
N-terminal leukemia. Nat Chem Biol 11(8):571–578. https://doi.org/10.1038/nchembio.1859
99. Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D,
Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL (2015)
Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature
525(7568):206–211. https://doi.org/10.1038/nature15251
100. Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T,
Wang J, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL,
Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J (2015) Pharmacologic
inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo.
Cancer Cell 27(4):589–602. https://doi.org/10.1016/j.ccell.2015.02.016
101. Zhou JX, Dhawan S, Fu H, Snyder E, Bottino R, Kundu S, Kim SK, Bhushan A (2013)
Combined modulation of polycomb and trithorax genes rejuvenates beta cell replication. J Clin
Invest 123(11):4849–4858. https://doi.org/10.1172/JCI69468
102. He S, Senter TJ, Pollock J, Han C, Upadhyay SK, Purohit T, Gogliotti RD, Lindsley CW,
Cierpicki T, Stauffer SR, Grembecka J (2014) High-affinity small-molecule inhibitors of the
menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein
interaction. J Med Chem 57(4):1543–1556. https://doi.org/10.1021/jm401868d
103. Keating ST, El-Osta A (2013) Transcriptional regulation by the Set7 lysine methyltransferase.
Epigenetics 8(4):361–372. https://doi.org/10.4161/epi.24234
104. Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA,
Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S,
Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS,
Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME,
Owen DR, Zaph C, Vedadi M, Arrowsmith CH (2014) (R)-PFI-2 is a potent and selective
inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci U S A 111(35):
12853–12858. https://doi.org/10.1073/pnas.1407358111
105. Niu Y, Shi D, Li L, Guo J, Liu H, Yao X (2017) Revealing inhibition difference between PFI-2
enantiomers against SETD7 by molecular dynamics simulations, binding free energy calculations and unbinding pathway analysis. Sci Rep 7:46547. https://doi.org/10.1038/srep46547
106. Francis NJ, Rowlands M, Workman P, Jones K, Aherne W (2012) Small-molecule inhibitors
of the protein methyltransferase SET7/9 identified in a high-throughput screen. J Biomol
Screen 17(8):1102–1109. https://doi.org/10.1177/1087057112452137
107. Mori S, Iwase K, Iwanami N, Tanaka Y, Kagechika H, Hirano T (2010) Development of novel
bisubstrate-type inhibitors of histone methyltransferase SET7/9. Bioorg Med Chem 18(23):
8158–8166. https://doi.org/10.1016/j.bmc.2010.10.022
108. Meng F, Cheng S, Ding H, Liu S, Liu Y, Zhu K, Chen S, Lu J, Xie Y, Li L, Liu R, Shi Z,
Zhou Y, Liu YC, Zheng M, Jiang H, Lu W, Liu H, Luo C (2015) Discovery and optimization
of novel, selective histone methyltransferase SET7 inhibitors by pharmacophore- and dockingbased virtual screening. J Med Chem 58(20):8166–8181. https://doi.org/10.1021/acs.
jmedchem.5b01154
109. Takemoto Y, Ito A, Niwa H, Okamura M, Fujiwara T, Hirano T, Handa N, Umehara T,
Sonoda T, Ogawa K, Tariq M, Nishino N, Dan S, Kagechika H, Yamori T, Yokoyama S,
Yoshida M (2016) Identification of cyproheptadine as an inhibitor of SET domain containing
lysine methyltransferase 7/9 (Set7/9) that regulates estrogen-dependent transcription. J Med
Chem 59(8):3650–3660. https://doi.org/10.1021/acs.jmedchem.5b01732
Lysine Methyltransferases and Their Inhibitors
155