1 Introduction
Discovery and development of new drugs is a complex, expensive, and
time-consuming expedition that requires high R&D costs and extensive clinical
testing. Developing a drug may take a span of 10–15 years, with a cost of several
hundred million dollars [1]. Hitherto 90% of lead molecules end up in failure [2]
owing to a number of factors including problematic functionalities, solubility at
relevant concentrations, toxicity, off-target effects, etc. Epigenetic drug discovery is
emerging as a promising therapeutics for small-molecule modulation of various
metabolic, neurodegenerative, and cardiovascular diseases. The field of epigenetics
is relatively new and growing quickly. The word epigenetics is derived from Greek
prefix: ‘ἐpί-’ meaning ‘above,’ and thereby, the term ‘epigenetics’ literally
describes the regulation at a level above genetic mechanisms. While all cells in an
organism share identical genome, they are able to maintain unique physical characteristics and biological functions. The characteristics of a cell are determined by
DNA sequence as well as gene expression pattern. Since DNA sequence remains
the same in all cell types, the key role in cell fate is determined by epigenetics.
Many non-specific external stimuli such as temperature, viral infections, bacteria,
and diet can affect the DNA packing [3, 4] and as a result influence epigenetic
states, impacting cellular phenotype without disrupting nucleotide sequence.
Epigenetic changes are responsible for the cellular plasticity and enable cellular
reprogramming and environmental responses. Epigenetic mechanisms play the
critical role in diseases related to diet, lifestyle, environmental exposures to
chemicals, toxins, etc., and, thus, offer a robust platform to explore therapeutic
potential in various diseases (Table 1). The epigenetic states of a cell are dynamic
in nature and can be manipulated by targeting the molecular factors associated with
a disease. Chromatin remodeling via ATP-dependent processes, regulation by
noncoding RNAs, DNA methylation, histone acetylation, and histone methylation
are some of the key mechanisms involved in epigenetic gene regulation [5]. The
recent advances in epigenetic mechanisms, gene expression control, and cellular
functions have prompted the researchers to develop small-molecule inhibitors to
target these processes. The successful approval of many epigenetic drugs is timely
and promising. Pharmaceutical companies endorse this growing interest with huge
investments in order to explore new epigenetic drugs. According to recent market
reports, epigenetic drugs and diagnostic technology market are estimated to be
worth US$5.7 billion by 2018 [6]. Many existing drugs significantly affect the
epigenetic events [7, 8] during its disease-modifying action and further validate its
uniqueness as drug target. A recent study has shown that of all the FDA-approved
drugs, 1%, show significant epigenetic activity [9].
Despite the successful approval of epi-drugs, the druggability of many of the
epigenetic modulators remains challenging. Many factors such as selectivity,
poly-pharmacology, drug combination, toxicity, and target ‘confidence’ need to be
addressed. The new generation of epi-drugs is expected to be more selective and
specific with defined drug targets. Considering the increasing rate of failures in drug
248
S. Loharch et al.
Discovery and development of new drugs is a complex, expensive, and
time-consuming expedition that requires high R&D costs and extensive clinical
testing. Developing a drug may take a span of 10–15 years, with a cost of several
hundred million dollars [1]. Hitherto 90% of lead molecules end up in failure [2]
owing to a number of factors including problematic functionalities, solubility at
relevant concentrations, toxicity, off-target effects, etc. Epigenetic drug discovery is
emerging as a promising therapeutics for small-molecule modulation of various
metabolic, neurodegenerative, and cardiovascular diseases. The field of epigenetics
is relatively new and growing quickly. The word epigenetics is derived from Greek
prefix: ‘ἐpί-’ meaning ‘above,’ and thereby, the term ‘epigenetics’ literally
describes the regulation at a level above genetic mechanisms. While all cells in an
organism share identical genome, they are able to maintain unique physical characteristics and biological functions. The characteristics of a cell are determined by
DNA sequence as well as gene expression pattern. Since DNA sequence remains
the same in all cell types, the key role in cell fate is determined by epigenetics.
Many non-specific external stimuli such as temperature, viral infections, bacteria,
and diet can affect the DNA packing [3, 4] and as a result influence epigenetic
states, impacting cellular phenotype without disrupting nucleotide sequence.
Epigenetic changes are responsible for the cellular plasticity and enable cellular
reprogramming and environmental responses. Epigenetic mechanisms play the
critical role in diseases related to diet, lifestyle, environmental exposures to
chemicals, toxins, etc., and, thus, offer a robust platform to explore therapeutic
potential in various diseases (Table 1). The epigenetic states of a cell are dynamic
in nature and can be manipulated by targeting the molecular factors associated with
a disease. Chromatin remodeling via ATP-dependent processes, regulation by
noncoding RNAs, DNA methylation, histone acetylation, and histone methylation
are some of the key mechanisms involved in epigenetic gene regulation [5]. The
recent advances in epigenetic mechanisms, gene expression control, and cellular
functions have prompted the researchers to develop small-molecule inhibitors to
target these processes. The successful approval of many epigenetic drugs is timely
and promising. Pharmaceutical companies endorse this growing interest with huge
investments in order to explore new epigenetic drugs. According to recent market
reports, epigenetic drugs and diagnostic technology market are estimated to be
worth US$5.7 billion by 2018 [6]. Many existing drugs significantly affect the
epigenetic events [7, 8] during its disease-modifying action and further validate its
uniqueness as drug target. A recent study has shown that of all the FDA-approved
drugs, 1%, show significant epigenetic activity [9].
Despite the successful approval of epi-drugs, the druggability of many of the
epigenetic modulators remains challenging. Many factors such as selectivity,
poly-pharmacology, drug combination, toxicity, and target ‘confidence’ need to be
addressed. The new generation of epi-drugs is expected to be more selective and
specific with defined drug targets. Considering the increasing rate of failures in drug
248
S. Loharch et al.