blocks the androgen receptor-mediated transcriptional programmes in both
androgen-sensitive and castration-resistant prostate tumour cells and reduces the
growth of the prostate cancer in the xenograft model LuCaP-77 [113].
Identified through a high-throughput screening as a single-digit micromolar
Tip60 inhibitor (IC 50 ¼ 2 μM), the bis-isothiazole disulphide NU9056 (18), when
assayed in prostate cancer cells, induced a time- and concentration-dependent
decrease in histone acetylation and a significant amount of apoptosis [115].
Recently, by means of a fragment screening approach, has been reported the
fragment 4-amino-1-naphthol (19, 4A1N) as a micromolar inhibitor of MOF
(IC 50 ¼ 9.7 μM), with K i values that suggest an inhibition occurring mainly through
the interaction with the acetylated form of the enzyme [116]. Despite unselective
over PCAF (IC 50 ¼ 3.6 μM) and p300 (IC 50 ¼ 1.4 μM), 19 can be considered an
interesting starting point for the development of more active and selective MOFi.
9 Conclusions and Perspectives
Despite more than 50 years have passed since the first discoveries about HAT
activity and numerous studies over this timeframe have disclosed the structural
features of HATs and their involvement in various pathological conditions, with
only one very recent exception, no in vivo potent and selective HATi are available so
far. In fact, despite virtual screening and structure-based drug design approaches, by
using both enzyme and enzyme-(co)substrates crystallographic structures, have been
successful in providing some promising HATi, there is still the necessity to develop
more potent (particularly in cells and in vivo) and selective (between HAT subtypes
and between HAT and other enzymes) inhibitors that could work either as chemical
Fig. 6 Binding mode of
compound 17 derived from
the co-crystal structure
with p300
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
113
androgen-sensitive and castration-resistant prostate tumour cells and reduces the
growth of the prostate cancer in the xenograft model LuCaP-77 [113].
Identified through a high-throughput screening as a single-digit micromolar
Tip60 inhibitor (IC 50 ¼ 2 μM), the bis-isothiazole disulphide NU9056 (18), when
assayed in prostate cancer cells, induced a time- and concentration-dependent
decrease in histone acetylation and a significant amount of apoptosis [115].
Recently, by means of a fragment screening approach, has been reported the
fragment 4-amino-1-naphthol (19, 4A1N) as a micromolar inhibitor of MOF
(IC 50 ¼ 9.7 μM), with K i values that suggest an inhibition occurring mainly through
the interaction with the acetylated form of the enzyme [116]. Despite unselective
over PCAF (IC 50 ¼ 3.6 μM) and p300 (IC 50 ¼ 1.4 μM), 19 can be considered an
interesting starting point for the development of more active and selective MOFi.
9 Conclusions and Perspectives
Despite more than 50 years have passed since the first discoveries about HAT
activity and numerous studies over this timeframe have disclosed the structural
features of HATs and their involvement in various pathological conditions, with
only one very recent exception, no in vivo potent and selective HATi are available so
far. In fact, despite virtual screening and structure-based drug design approaches, by
using both enzyme and enzyme-(co)substrates crystallographic structures, have been
successful in providing some promising HATi, there is still the necessity to develop
more potent (particularly in cells and in vivo) and selective (between HAT subtypes
and between HAT and other enzymes) inhibitors that could work either as chemical
Fig. 6 Binding mode of
compound 17 derived from
the co-crystal structure
with p300
Histone Acetyltransferase Enzymes: From Biological Implications to Most. . .
113