3.4 New Approaches to DNMT Inhibitor Design
Finally, a very promising approach is the design of dual inhibitors [97]. By modifying BIX-01294, inhibitor of histone H3 lysine 9 methyltransferase G9A, Rotili
et al. identified new quinazoline derivatives as inhibitors of DNMT3A with activity
in cancer cells (cpd 14 (27) Fig. 3 [98]). José-Enériz et al. successfully modulated
this family of G9A and DNMT inhibitors to obtain a dual G9A-DNMT1 inhibitor,
CMC-272 (23) (Fig. 3), with anti-leukaemia effect in an in vivo model of mice
engrafted with ALL-derived CEMO-1 cells [99]. This is the first example of DNMT
dual inhibitors active in vivo. Other dual inhibitors are currently being explored,
such as (22) (Fig. 3), resulting from chemical optimisations based on HDAC
inhibitors [100].
Taken together, the transition state and bisubstrate analogues, as well as dual
inhibitors, are interesting chemical approaches that need to be further explored to
obtain new, potent and selective inhibitors of DNMT. Another strategy worth
exploring is to develop protein-protein interaction inhibitors (PPI) for DNMTs.
PPIs have been successful for other epigenetic targets, and it is worthwhile since
the DNMTs are involved in protein complexes that direct DNA methylation
[101, 102]. For example, the inhibition of the DNMT1/CFP1 interface with peptides
was shown to affect methylation level of cancer cells and to synergise with
temozolomide [103]. Most recently, Ye et al. determined the crystal structure of
DNMT1 in two different states and suggest the possibility to design inhibitors of the
conformational transition necessary for DNMT1 activity [30].
4 TET Enzymes
Methylation at the 5-position of cytosine (5mC) is recognised by the TET enzymes
that catalyse the oxidation of 5mC in a cascade of iterative steps (Fig. 1). TETs are
part of the oxygenase superfamily that uses Fe(II) for catalysis, using O 2 and
2-oxoglutarate (2OG, 3) as cofactors, to generate the oxidised substrate, CO 2 and
succinate (4) [6]. Recent developments reveal that the 5-methyl oxidations at
cytosines play an extensive role in epigenetic regulation and key steps in the DNA
demethylation pathways. Studies have shown that TETs are fundamental in mammal
development and mutations, or overexpression of the protein is linked to various
diseases.
4.1 Discovery and Biological Roles of TETs
DNA methylation is a well-established modification, and it has long been known that
passive dilution alone cannot fully account for the rapid rate of genome methyl
266
R. Belle et al.
Finally, a very promising approach is the design of dual inhibitors [97]. By modifying BIX-01294, inhibitor of histone H3 lysine 9 methyltransferase G9A, Rotili
et al. identified new quinazoline derivatives as inhibitors of DNMT3A with activity
in cancer cells (cpd 14 (27) Fig. 3 [98]). José-Enériz et al. successfully modulated
this family of G9A and DNMT inhibitors to obtain a dual G9A-DNMT1 inhibitor,
CMC-272 (23) (Fig. 3), with anti-leukaemia effect in an in vivo model of mice
engrafted with ALL-derived CEMO-1 cells [99]. This is the first example of DNMT
dual inhibitors active in vivo. Other dual inhibitors are currently being explored,
such as (22) (Fig. 3), resulting from chemical optimisations based on HDAC
inhibitors [100].
Taken together, the transition state and bisubstrate analogues, as well as dual
inhibitors, are interesting chemical approaches that need to be further explored to
obtain new, potent and selective inhibitors of DNMT. Another strategy worth
exploring is to develop protein-protein interaction inhibitors (PPI) for DNMTs.
PPIs have been successful for other epigenetic targets, and it is worthwhile since
the DNMTs are involved in protein complexes that direct DNA methylation
[101, 102]. For example, the inhibition of the DNMT1/CFP1 interface with peptides
was shown to affect methylation level of cancer cells and to synergise with
temozolomide [103]. Most recently, Ye et al. determined the crystal structure of
DNMT1 in two different states and suggest the possibility to design inhibitors of the
conformational transition necessary for DNMT1 activity [30].
4 TET Enzymes
Methylation at the 5-position of cytosine (5mC) is recognised by the TET enzymes
that catalyse the oxidation of 5mC in a cascade of iterative steps (Fig. 1). TETs are
part of the oxygenase superfamily that uses Fe(II) for catalysis, using O 2 and
2-oxoglutarate (2OG, 3) as cofactors, to generate the oxidised substrate, CO 2 and
succinate (4) [6]. Recent developments reveal that the 5-methyl oxidations at
cytosines play an extensive role in epigenetic regulation and key steps in the DNA
demethylation pathways. Studies have shown that TETs are fundamental in mammal
development and mutations, or overexpression of the protein is linked to various
diseases.
4.1 Discovery and Biological Roles of TETs
DNA methylation is a well-established modification, and it has long been known that
passive dilution alone cannot fully account for the rapid rate of genome methyl
266
R. Belle et al.