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86. Waters NJ, Smith SA, Olhava EJ, Duncan KW, Burton RD, O’Neill J, Rodrigue ME, Pollock
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87. Basavapathruni A, Olhava EJ, Daigle SR, Therkelsen CA, Jin L, Boriack-Sjodin PA, Allain
CJ, Klaus CR, Raimondi A, Scott MP, Dovletoglou A, Richon VM, Pollock RM, Copeland
RA, Moyer MP, Chesworth R, Pearson PG, Waters NJ (2014) Nonclinical pharmacokinetics
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Biopharm Drug Dispos 35(4):237–252. https://doi.org/10.1002/bdd.1889
88. Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y (2011) Selective
inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J Am Chem Soc 133(42):16746–16749. https://doi.org/10.1021/ja206312b
89. Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, Tiedt R, Stauffer F
(2016) Optimization of a fragment-based screening hit toward potent DOT1L inhibitors
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org/10.1021/acsmedchemlett.6b00168
90. Chen C, Zhu H, Stauffer F, Caravatti G, Vollmer S, Machauer R, Holzer P, Mobitz H,
Scheufler C, Klumpp M, Tiedt R, Beyer KS, Calkins K, Guthy D, Kiffe M, Zhang J, Gaul
C (2016) Discovery of novel Dot1L inhibitors through a structure-based fragmentation
approach. ACS Med Chem Lett 7(8):735–740. https://doi.org/10.1021/acsmedchemlett.
6b00167
91. Mobitz H, Machauer R, Holzer P, Vaupel A, Stauffer F, Ragot C, Caravatti G, Scheufler C,
Fernandez C, Hommel U, Tiedt R, Beyer KS, Chen C, Zhu H, Gaul C (2017) Discovery of
potent, selective, and structurally novel Dot1L inhibitors by a fragment linking approach.
ACS Med Chem Lett 8(3):338–343. https://doi.org/10.1021/acsmedchemlett.6b00519
92. Rao RC, Dou Y (2015) Hijacked in cancer: the KMT2 (MLL) family of methyltransferases.
Nat Rev Cancer 15(6):334–346. https://doi.org/10.1038/nrc3929
93. Li Y, Han J, Zhang Y, Cao F, Liu Z, Li S, Wu J, Hu C, Wang Y, Shuai J, Chen J, Cao L, Li D,
Shi P, Tian C, Zhang J, Dou Y, Li G, Chen Y, Lei M (2016) Structural basis for activity
regulation of MLL family methyltransferases. Nature 530(7591):447–452. https://doi.org/10.
1038/nature16952
94. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG (2006)
Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol
Biol 13(8):713–719. https://doi.org/10.1038/nsmb1128
95. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML
(2005) The menin tumor suppressor protein is an essential oncogenic cofactor for
MLL-associated leukemogenesis. Cell 123(2):207–218. https://doi.org/10.1016/j.cell.2005.
09.025
96. Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, Liu L, Chen Y, Ouillette P, Zhu J, Hess JL,
Atadja P, Lei M, Qin ZS, Malek S, Wang S, Dou Y (2014) Targeting MLL1 H3K4
methyltransferase activity in mixed-lineage leukemia. Mol Cell 53(2):247–261. https://doi.
org/10.1016/j.molcel.2013.12.001
97. Karatas H, Li Y, Liu L, Ji J, Lee S, Chen Y, Yang J, Huang L, Bernard D, Xu J, Townsend EC,
Cao F, Ran X, Li X, Wen B, Sun D, Stuckey JA, Lei M, Dou Y, Wang S (2017) Discovery of a
highly potent, cell-permeable macrocyclic peptidomimetic (MM-589) targeting the WD repeat
154
G. Stazi et al.
H3K79 methyltransferase Dot1l. Leukemia 27(4):813–822. https://doi.org/10.1038/leu.2012.
327
85. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain
CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA,
Richon VM, Pollock RM (2013) Potent inhibition of DOT1L as treatment of MLL-fusion
leukemia. Blood 122(6):1017–1025. https://doi.org/10.1182/blood-2013-04-497644
86. Waters NJ, Smith SA, Olhava EJ, Duncan KW, Burton RD, O’Neill J, Rodrigue ME, Pollock
RM, Moyer MP, Chesworth R (2016) Metabolism and disposition of the DOT1L inhibitor,
pinometostat (EPZ-5676), in rat, dog and human. Cancer Chemother Pharmacol 77(1):43–62.
https://doi.org/10.1007/s00280-015-2929-y
87. Basavapathruni A, Olhava EJ, Daigle SR, Therkelsen CA, Jin L, Boriack-Sjodin PA, Allain
CJ, Klaus CR, Raimondi A, Scott MP, Dovletoglou A, Richon VM, Pollock RM, Copeland
RA, Moyer MP, Chesworth R, Pearson PG, Waters NJ (2014) Nonclinical pharmacokinetics
and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor.
Biopharm Drug Dispos 35(4):237–252. https://doi.org/10.1002/bdd.1889
88. Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, Prasad BV, Song Y (2011) Selective
inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J Am Chem Soc 133(42):16746–16749. https://doi.org/10.1021/ja206312b
89. Scheufler C, Mobitz H, Gaul C, Ragot C, Be C, Fernandez C, Beyer KS, Tiedt R, Stauffer F
(2016) Optimization of a fragment-based screening hit toward potent DOT1L inhibitors
interacting in an induced binding pocket. ACS Med Chem Lett 7(8):730–734. https://doi.
org/10.1021/acsmedchemlett.6b00168
90. Chen C, Zhu H, Stauffer F, Caravatti G, Vollmer S, Machauer R, Holzer P, Mobitz H,
Scheufler C, Klumpp M, Tiedt R, Beyer KS, Calkins K, Guthy D, Kiffe M, Zhang J, Gaul
C (2016) Discovery of novel Dot1L inhibitors through a structure-based fragmentation
approach. ACS Med Chem Lett 7(8):735–740. https://doi.org/10.1021/acsmedchemlett.
6b00167
91. Mobitz H, Machauer R, Holzer P, Vaupel A, Stauffer F, Ragot C, Caravatti G, Scheufler C,
Fernandez C, Hommel U, Tiedt R, Beyer KS, Chen C, Zhu H, Gaul C (2017) Discovery of
potent, selective, and structurally novel Dot1L inhibitors by a fragment linking approach.
ACS Med Chem Lett 8(3):338–343. https://doi.org/10.1021/acsmedchemlett.6b00519
92. Rao RC, Dou Y (2015) Hijacked in cancer: the KMT2 (MLL) family of methyltransferases.
Nat Rev Cancer 15(6):334–346. https://doi.org/10.1038/nrc3929
93. Li Y, Han J, Zhang Y, Cao F, Liu Z, Li S, Wu J, Hu C, Wang Y, Shuai J, Chen J, Cao L, Li D,
Shi P, Tian C, Zhang J, Dou Y, Li G, Chen Y, Lei M (2016) Structural basis for activity
regulation of MLL family methyltransferases. Nature 530(7591):447–452. https://doi.org/10.
1038/nature16952
94. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG (2006)
Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol
Biol 13(8):713–719. https://doi.org/10.1038/nsmb1128
95. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML
(2005) The menin tumor suppressor protein is an essential oncogenic cofactor for
MLL-associated leukemogenesis. Cell 123(2):207–218. https://doi.org/10.1016/j.cell.2005.
09.025
96. Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, Liu L, Chen Y, Ouillette P, Zhu J, Hess JL,
Atadja P, Lei M, Qin ZS, Malek S, Wang S, Dou Y (2014) Targeting MLL1 H3K4
methyltransferase activity in mixed-lineage leukemia. Mol Cell 53(2):247–261. https://doi.
org/10.1016/j.molcel.2013.12.001
97. Karatas H, Li Y, Liu L, Ji J, Lee S, Chen Y, Yang J, Huang L, Bernard D, Xu J, Townsend EC,
Cao F, Ran X, Li X, Wen B, Sun D, Stuckey JA, Lei M, Dou Y, Wang S (2017) Discovery of a
highly potent, cell-permeable macrocyclic peptidomimetic (MM-589) targeting the WD repeat
154
G. Stazi et al.