Among the top-scored 48 compounds, which were subjected to in vitro screening,
12 compounds showed a micromolar activity against JARIDA. Further structural
optimization of one of the identified hits, namely, a 2,4-diaminopyrimidne derivative,
resulted in the submicromolar inhibitor 42 (Fig. 8), which bears a pyrimidinecarboxylic acid scaffold, a core structure already known from JMJD2 inhibitors.
Cellular testing showed that the compound is able to increase the level of
H3K4me3 (trimethylated lysine 4 of histone 3) in a dose-dependent manner.
6 Summary
Despite many technical challenges, structure-based design plays an important role in
drug discovery. As a steadily growing number of epigenetic targets are biologically
and structurally characterized, structure-based methods are more and more applied to
design specific inhibitors in order to elucidate their therapeutic potential. Ligand
docking and scoring technologies have steadily improved, and the importance of the
adequate validation of pragmatic VS protocols is now well recognized. While both
ligand- and structure-based approaches have already demonstrated their worth in the
identification of novel lead compounds for epigenetic targets, there is still the
challenge to improve the predictive accuracy of scoring functions, particularly to
enable scoring-based methods to have a greater impact in guiding lead optimization.
Acknowledgments We thank the European COST actions “Epigenetic Chemical Biology”
(CM1406) and “MuTaLig” (CA15135) for support.
Compliance with Ethical Standards
Conflict of Interest: The authors declare that they have no conflict of interest.
Ethical Approval: All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national research committee and
with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent: Informed consent was obtained from all individual participants included in the
study.
References
1. Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286
(5439):481–486. https://doi.org/10.1126/science.286.5439.481
2. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705.
https://doi.org/10.1016/j.cell.2007.02.005
3. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich
NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA
inhibitors. Nature 401(6749):188–193. https://doi.org/10.1038/43710
Structure-Based Design of Epigenetic Inhibitors
475
12 compounds showed a micromolar activity against JARIDA. Further structural
optimization of one of the identified hits, namely, a 2,4-diaminopyrimidne derivative,
resulted in the submicromolar inhibitor 42 (Fig. 8), which bears a pyrimidinecarboxylic acid scaffold, a core structure already known from JMJD2 inhibitors.
Cellular testing showed that the compound is able to increase the level of
H3K4me3 (trimethylated lysine 4 of histone 3) in a dose-dependent manner.
6 Summary
Despite many technical challenges, structure-based design plays an important role in
drug discovery. As a steadily growing number of epigenetic targets are biologically
and structurally characterized, structure-based methods are more and more applied to
design specific inhibitors in order to elucidate their therapeutic potential. Ligand
docking and scoring technologies have steadily improved, and the importance of the
adequate validation of pragmatic VS protocols is now well recognized. While both
ligand- and structure-based approaches have already demonstrated their worth in the
identification of novel lead compounds for epigenetic targets, there is still the
challenge to improve the predictive accuracy of scoring functions, particularly to
enable scoring-based methods to have a greater impact in guiding lead optimization.
Acknowledgments We thank the European COST actions “Epigenetic Chemical Biology”
(CM1406) and “MuTaLig” (CA15135) for support.
Compliance with Ethical Standards
Conflict of Interest: The authors declare that they have no conflict of interest.
Ethical Approval: All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national research committee and
with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent: Informed consent was obtained from all individual participants included in the
study.
References
1. Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286
(5439):481–486. https://doi.org/10.1126/science.286.5439.481
2. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705.
https://doi.org/10.1016/j.cell.2007.02.005
3. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich
NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA
inhibitors. Nature 401(6749):188–193. https://doi.org/10.1038/43710
Structure-Based Design of Epigenetic Inhibitors
475