key advances, challenges, possible future opportunities, and directions, regarding
KMT modulation.
In the last years, the resolution of KMT crystal structures provided rational bases
for designing highly selective inhibitors. Here, we have summarized the discovery
and validation of selective inhibitors of KMTs focusing on the most potent, selective, and well-characterized small molecules with robust on-target activities in cells.
Some of the molecules presented are now in a more advanced stage of development such as the first inhibitors of DOT1L and EZH2 that entered the clinical arena
for diseases such as leukemia, lymphoma, and SCLC.
We have seen significant progress, in the KMT inhibitor field; however for some
KMTs, such as the MMSET (NSD-2) or the MLL family, the biological function in
both physiological and pathological processes is not yet fully understood, partly due
to the lack of selective inhibitors of these PMTs.
Furthermore, a better understanding of the dynamic interactions of the aforementioned proteins is a very desirable goal, possibly using selective inhibitors able to
dissect highly homologous KMTs.
In the years to come, an amazing development can be expected as a lot of
research groups are actively developing valuable chemical tools to better understand
the biological functions of KMTs and test therapeutic hypotheses regarding these
proteins.
Compliance with Ethical Standards
Conflict of Interest: The authors declare no conflict of interest.
Ethical Approval: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Bennett RL, Licht JD (2018) Targeting epigenetics in cancer. Annu Rev Pharmacol Toxicol
58:187–207. https://doi.org/10.1146/annurev-pharmtox-010716-105106
2. Ribich S, Harvey D, Copeland RA (2017) Drug discovery and chemical biology of cancer
epigenetics. Cell Chem Biol 24(9):1120–1147. https://doi.org/10.1016/j.chembiol.2017.08.
020
3. Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL
(2010) G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 285(13):
9636–9641. https://doi.org/10.1074/jbc.M109.062588
4. Inagawa M, Nakajima K, Makino T, Ogawa S, Kojima M, Ito S, Ikenishi A, Hayashi T,
Schwartz RJ, Nakamura K, Obayashi T, Tachibana M, Shinkai Y, Maeda K, MiyagawaTomita S, Takeuchi T (2013) Histone H3 lysine 9 methyltransferases, G9a and GLP are
essential for cardiac morphogenesis. Mech Dev 130(11–12):519–531. https://doi.org/10.1016/
j.mod.2013.07.002
5. Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA,
Herreros-Villanueva M, Gress TM, Ellenrieder V, Bujanda L, Kim DH, Kozikowski AP,
Lysine Methyltransferases and Their Inhibitors
147
KMT modulation.
In the last years, the resolution of KMT crystal structures provided rational bases
for designing highly selective inhibitors. Here, we have summarized the discovery
and validation of selective inhibitors of KMTs focusing on the most potent, selective, and well-characterized small molecules with robust on-target activities in cells.
Some of the molecules presented are now in a more advanced stage of development such as the first inhibitors of DOT1L and EZH2 that entered the clinical arena
for diseases such as leukemia, lymphoma, and SCLC.
We have seen significant progress, in the KMT inhibitor field; however for some
KMTs, such as the MMSET (NSD-2) or the MLL family, the biological function in
both physiological and pathological processes is not yet fully understood, partly due
to the lack of selective inhibitors of these PMTs.
Furthermore, a better understanding of the dynamic interactions of the aforementioned proteins is a very desirable goal, possibly using selective inhibitors able to
dissect highly homologous KMTs.
In the years to come, an amazing development can be expected as a lot of
research groups are actively developing valuable chemical tools to better understand
the biological functions of KMTs and test therapeutic hypotheses regarding these
proteins.
Compliance with Ethical Standards
Conflict of Interest: The authors declare no conflict of interest.
Ethical Approval: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Bennett RL, Licht JD (2018) Targeting epigenetics in cancer. Annu Rev Pharmacol Toxicol
58:187–207. https://doi.org/10.1146/annurev-pharmtox-010716-105106
2. Ribich S, Harvey D, Copeland RA (2017) Drug discovery and chemical biology of cancer
epigenetics. Cell Chem Biol 24(9):1120–1147. https://doi.org/10.1016/j.chembiol.2017.08.
020
3. Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL
(2010) G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem 285(13):
9636–9641. https://doi.org/10.1074/jbc.M109.062588
4. Inagawa M, Nakajima K, Makino T, Ogawa S, Kojima M, Ito S, Ikenishi A, Hayashi T,
Schwartz RJ, Nakamura K, Obayashi T, Tachibana M, Shinkai Y, Maeda K, MiyagawaTomita S, Takeuchi T (2013) Histone H3 lysine 9 methyltransferases, G9a and GLP are
essential for cardiac morphogenesis. Mech Dev 130(11–12):519–531. https://doi.org/10.1016/
j.mod.2013.07.002
5. Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA,
Herreros-Villanueva M, Gress TM, Ellenrieder V, Bujanda L, Kim DH, Kozikowski AP,
Lysine Methyltransferases and Their Inhibitors
147