modulating immunological and metabolic pathways and therefore may have a
crucial role in maintaining energy homeostasis [71]. To date, the role of HDACs
in these processes is well known. In contrast, the functions of HAT members are not
as well explored as HDACs.
5 HAT Inhibitors
In the past 20 years, a great amount of evidence about the involvement of aberrant
histone protein acetylation in development of different diseases has stimulated a
continuous research on HATi as potential therapeutics or at least as chemical probes
for better understanding of HAT biology. To date, despite the great efforts made by
different research groups into finding small molecule HATi, only a few promising
compounds have been identified. By a medicinal chemistry point of view, according
to origin and mechanism of action, HATi can be divided into three main groups:
bisubstrate inhibitors, natural inhibitors and related (semi)synthetic derivatives and
fully synthetic inhibitors (Table 2).
6 Bisubstrate Inhibitors
The bisubstrate inhibitors are HAT substrate mimics that consist of two moieties
connected by spacers of variable length: the coenzyme A, resembling the natural
co-substrate acetyl-CoA, and a (pseudo)peptide portion, mimicking the lysinecontaining histone substrate sequences (Fig. 3).
In the so-called Lys-CoA (1), CoA is connected to the ε-amino group of a Nacetyl-lysine through a carboxymethylene linker, while the lysine carboxylic acid is
converted into a primary amide. Lys-CoA shows activity towards p300 in the
sub-micromolar range (IC 50 ¼ 0.5 μM), with a selectivity over PCAF
(IC 50 ¼ 200 μM) of 400 times, that can be ascribed to the different catalytic
mechanism of the two HATs [72]. In 2008, has been reported the co-crystal structure
of 1 bound within the p300 catalytic site, shading light into the interactions that are
crucial for the inhibition [73].
The main medicinal chemistry approach pursued to modulate selectivity and
affinity of bisubstrate inhibitors has been to vary the sequence and length of the
peptide chain bound to Lys-CoA. In this way have been obtained the peptide
2 (H3-CoA-20) that, resembling the K14-containing sequence of histone H3 (the
main PCAF substrate), is a sub-micromolar inhibitor of this enzyme(IC 50 ¼ 0.3 μM)
[72] and the peptide 3 that, mimicking the K16-containing sequence of histone H4
(the main substrate of many MYST family enzymes), is a micromolar inhibitor of
Tip60 (IC 50 ¼ 17.6 μM) and p300 (IC 50 ¼ 6.62 μM) [74]. Unfortunately, all these
compounds suffer from metabolic instability and low cell permeability, primarily
due to their (pseudo)peptidic nature and the presence of phosphate groups within the
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
103
crucial role in maintaining energy homeostasis [71]. To date, the role of HDACs
in these processes is well known. In contrast, the functions of HAT members are not
as well explored as HDACs.
5 HAT Inhibitors
In the past 20 years, a great amount of evidence about the involvement of aberrant
histone protein acetylation in development of different diseases has stimulated a
continuous research on HATi as potential therapeutics or at least as chemical probes
for better understanding of HAT biology. To date, despite the great efforts made by
different research groups into finding small molecule HATi, only a few promising
compounds have been identified. By a medicinal chemistry point of view, according
to origin and mechanism of action, HATi can be divided into three main groups:
bisubstrate inhibitors, natural inhibitors and related (semi)synthetic derivatives and
fully synthetic inhibitors (Table 2).
6 Bisubstrate Inhibitors
The bisubstrate inhibitors are HAT substrate mimics that consist of two moieties
connected by spacers of variable length: the coenzyme A, resembling the natural
co-substrate acetyl-CoA, and a (pseudo)peptide portion, mimicking the lysinecontaining histone substrate sequences (Fig. 3).
In the so-called Lys-CoA (1), CoA is connected to the ε-amino group of a Nacetyl-lysine through a carboxymethylene linker, while the lysine carboxylic acid is
converted into a primary amide. Lys-CoA shows activity towards p300 in the
sub-micromolar range (IC 50 ¼ 0.5 μM), with a selectivity over PCAF
(IC 50 ¼ 200 μM) of 400 times, that can be ascribed to the different catalytic
mechanism of the two HATs [72]. In 2008, has been reported the co-crystal structure
of 1 bound within the p300 catalytic site, shading light into the interactions that are
crucial for the inhibition [73].
The main medicinal chemistry approach pursued to modulate selectivity and
affinity of bisubstrate inhibitors has been to vary the sequence and length of the
peptide chain bound to Lys-CoA. In this way have been obtained the peptide
2 (H3-CoA-20) that, resembling the K14-containing sequence of histone H3 (the
main PCAF substrate), is a sub-micromolar inhibitor of this enzyme(IC 50 ¼ 0.3 μM)
[72] and the peptide 3 that, mimicking the K16-containing sequence of histone H4
(the main substrate of many MYST family enzymes), is a micromolar inhibitor of
Tip60 (IC 50 ¼ 17.6 μM) and p300 (IC 50 ¼ 6.62 μM) [74]. Unfortunately, all these
compounds suffer from metabolic instability and low cell permeability, primarily
due to their (pseudo)peptidic nature and the presence of phosphate groups within the
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
103