maintain the chromatin structure and allow dynamic movements between euchromatin and heterochromatin [4] (Fig. 1). Euchromatin is loosely packed, thereby
accessible to transcription machinery and genetically active. In contrast, the heterochromatin contains highly compact DNA in which case it is difficult to access by
transcription machinery and, consequently, is genetically inactive.
Epigenetic modifications
Alterations in chromatin structure and subsequent change in the gene expression are
achieved by two main mechanisms: (1) DNA methylation at cytidine residues and
(2) histone modifications. Histone modifications may include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation and siRNA-controlled gene
expression. These modifications lead to multiple chromatin states, creating combinatorial patterns of DNA and histone variant mark areas of distinct genome
functions [25]. Such patterns both reflect and influence chromatin-related processes,
mainly DNA replication, DNA repair, transcription, and chromosomal segregation.
The epigenetic proteins that facilitate such modifications can be divided into three
major categories based on their broad functions: (1) writers that embed epigenetic
marks on DNA or histones, (2) erasers that remove such marks, and (3) readers that
identify these marks (Fig. 1).
3 The First and Second Generation of Epi-Drugs
Research interest has grown exponentially within academia and industries to
develop therapeutic agents for cancer, aging, diabetes, neurodegenerative, and
cardiovascular disorders. This has led to the development of five successful
epi-drugs that have been approved by the FDA (Food and Drug Administration),
representing the first generation of epigenetic drugs (Table 2):
(1) 5-azacytidine (also known as Vidaza®): 5-Azacytidine is an analog of the
cytidine and was first synthesized about 40 years ago. Azacitidine inhibits
DNA methylation by stoichiometrically binding to DNMT1 (DNA methyltransferase 1). Azacitidine has been used primarily in the treatment of leukemia
and MDS (myelodysplastic syndrome).
(2) 5-aza-2′deoxycytidine (also known as decitabine or trade name: Dacogen®):
5-aza-2′deoxycytidine is also an analog of cytidine. Similar to Azacitidine, it
also inhibits DNMT1 (DNA methyltransferase 1) and exhibits clinical utility in
MDS (myelodysplastic syndrome) and leukemia.
(3) Vorinostat (chemical name: suberoylanilide hydroxamic acid, commercially
known as Zolinza®): Vorinostat is an inhibitor of class I and II HDACs (histone deacetylases). Vorinostat has been approved for the treatment of CTCL
(cutaneous T cell lymphoma).
Integrated Chemoinformatics Approaches …
251
accessible to transcription machinery and genetically active. In contrast, the heterochromatin contains highly compact DNA in which case it is difficult to access by
transcription machinery and, consequently, is genetically inactive.
Epigenetic modifications
Alterations in chromatin structure and subsequent change in the gene expression are
achieved by two main mechanisms: (1) DNA methylation at cytidine residues and
(2) histone modifications. Histone modifications may include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation and siRNA-controlled gene
expression. These modifications lead to multiple chromatin states, creating combinatorial patterns of DNA and histone variant mark areas of distinct genome
functions [25]. Such patterns both reflect and influence chromatin-related processes,
mainly DNA replication, DNA repair, transcription, and chromosomal segregation.
The epigenetic proteins that facilitate such modifications can be divided into three
major categories based on their broad functions: (1) writers that embed epigenetic
marks on DNA or histones, (2) erasers that remove such marks, and (3) readers that
identify these marks (Fig. 1).
3 The First and Second Generation of Epi-Drugs
Research interest has grown exponentially within academia and industries to
develop therapeutic agents for cancer, aging, diabetes, neurodegenerative, and
cardiovascular disorders. This has led to the development of five successful
epi-drugs that have been approved by the FDA (Food and Drug Administration),
representing the first generation of epigenetic drugs (Table 2):
(1) 5-azacytidine (also known as Vidaza®): 5-Azacytidine is an analog of the
cytidine and was first synthesized about 40 years ago. Azacitidine inhibits
DNA methylation by stoichiometrically binding to DNMT1 (DNA methyltransferase 1). Azacitidine has been used primarily in the treatment of leukemia
and MDS (myelodysplastic syndrome).
(2) 5-aza-2′deoxycytidine (also known as decitabine or trade name: Dacogen®):
5-aza-2′deoxycytidine is also an analog of cytidine. Similar to Azacitidine, it
also inhibits DNMT1 (DNA methyltransferase 1) and exhibits clinical utility in
MDS (myelodysplastic syndrome) and leukemia.
(3) Vorinostat (chemical name: suberoylanilide hydroxamic acid, commercially
known as Zolinza®): Vorinostat is an inhibitor of class I and II HDACs (histone deacetylases). Vorinostat has been approved for the treatment of CTCL
(cutaneous T cell lymphoma).
Integrated Chemoinformatics Approaches …
251