• Healthy cells are under strict
biochemical control for growth and
• In cancer, these regulatory processes
have gone awry, and cells grow and
• Class of anticancer agents:
• DNA cross-linking agents (Nitrogen
• Protein tyrosine kinase inhibitors
• Histone deacetylase inhibitors
3. Histones are packing material for DNA!
• In chromatins, DNA is wrapped around proteins
of which most are histones.
• Histones assist in DNA packaging and have a
• Histones have a high proportion of positively
charged amino acids (lysine and arginine) which
bind tightly to the negatively charged DNA.
• Four core histones H2A, H2B, H3, and H4 serve
to wrap DNA into nucleosomes.
• Nucleosomes is the repeating pattern of 8
histone proteins along the length of the
chromatin structure, with each octet associated
with 146 basepairs of DNA
• The linker histone H1 role
4. Histone Acetylation and Decatylaion
• Histone acetylation regulated by 2 protein families:
Histone acetyltransferase (HAT)
Histone deacetylase (HDAC)
o HDACs classified into:
Class I: HDAC 1, 2, 3, and 8 reside in nucleus
Class IIa: HDAC 4, 5, 7 and 9 shuttle between nucleus and cytoplasm
Class IIb: HDAC 6 and 10 shuttle between nucleus and cytoplasm
Class III: sirtuin protein, consists of 7 types of protein
Class IV: HDAC11 shuttles between nucleus and cytoplasm
The linker histone H1 directs the path of DNA between the adjacent nucleosomes that make up the chromatin fiber
This project is based upon our findings that different interdependent modifications might modulate the biological function of HDAC1, a class I histone deacetylase (Figure 2). Human HDACs are targets for cancer therapy. However, although the therapeutic efforts with HDAC inhibitors in the treatment of cancer are being pursued (Figure 3), the role of individual HDACs in tumor genesis remains to be elucidated. The overriding theme of our studies is to understand whether HDAC1 is a relevant target for tumor therapy. This is accompanied by a study aimed at determining the role of Class I HDACs and possibly Class II in the maintenance of tumors
Hydroxamic acid based differentiating and antiproliferative agents were among the first compounds to be identified as histone deacetylase inhibitors, and these agents helped to define the model pharmacophore for HDAC inhibitors.
Hydroxamic-acid containing HDAC inhibitors have been postulated to interact with the catalytic site of HDACs, thereby blocking substrate access to the active zinc ion at its base
This pharmacophore consists of a metal binding domain, which interacts with the active site, a linker domain, which occupies the channel, and a surface recognition domain, which interacts with residues on the edge of the active site
The linker domain can consist of linear or cyclic structures, either saturated or unsaturated, and the surface recognition domain is generally a hydrophobic group, most often aromatic.
SAHA is the first HDAC inhibitor to meet FDA approval for cancer treatment. The HDAC inhibitor SAHA was reported by Breslow and co-workers.
An important feature of SAHA is its ability to chelate the zinc ion in the active site through its CO and OH groups.
SAHA may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
SAHA inhibits HDAC activity by binding to the pocket of the catalytic site. The hydroxamic acid moiety of SAHA binds to a zinc atom (pink) allowing the rest of the molecule to lie along the surface of the HDLP protein
At this point inhibits histone deacetylase, an enzyme that compacts chromatin and represses gene transcription, by binding to its active site. This allows histone acetyltransferase to activate gene transcription by catalyzing the addition of acetyl groups to the amino tails of the nucleosome, resulting in chromatin uncoiling and activation of gene transcription