Transcript Vasodilates_MichaelEvans

Afsha Rais

In chromatins, DNA is wrapped around
proteins of which most are histones.

Histones assist in DNA packaging and
have a regulatory role.

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

Dimethyl sulfoxide (DMSO)
› Terminal differentiation of murine erythroleukemia cells
› Interest in Histone Deacetylase (HDAC) inhibitors
› Chromatin remodeling

SAHA made it!!
› Treat rare cancer cutaneous T-cell lymphoma (CTCL)

Antitumor action of compounds undergoing clinical trials
www.pharmadd.com/.../graphs/HDAC%20Inhib_lg.gif
The main
pharmacological
application
for HDAC inhibitors is
the
treatment of cancer.
How does cancer occur?
 Transcription therapy  treatment for
cancer
 2 enzymes in the cell

› Histone acetyltransferase (HAT)
› Histone deacetylase (HDAC)
 Histone deacetylase inhibitors (HDI)
 Importance

Histone acetylation – attachment of acetyl groups (-COCH3) to certain amino
acids of histone proteins; Histone deacetylation – the removal of acetyl groups.

HDACs have many functions such as regulation of gene transcription,
regulation of gene expression by deacetylating transcription factors, gene
slicing, differentiation, and participation in cell cycle regulation.
O
CH3
H2N
C
O
SCoA
H
HSCoA
N
HAT
N
H
HDAC
O
O
CH3
C
OH
N
H
H2O
lysine residue in the N-terminal
tails of histones
acetylated lysine residue
HAT = histone acetyltransferase
HDAC = histone deacetylase
O
Class I
HDAC -1, -2,
-3, -8
Class IIa
HDAC -4, -5,
-7, -9
Class IIb
HDAC -6, -10
Class II
HDAC
Classes
Class III
SIRT -1, -2, -3,
-4, -5, -6, -7
Class IV
HDAC 11

Class of compounds that interfere with the
function of histone deacetylase

4 classes of HDAC inhibitors
› A short-chain fatty acid
› Hydroxamic acid
› Cyclic tetrapeptides
O
R
C
N
OH
H
a hydroxamic acid
› Benzamides

Phenylbutyrate
› One of the first HDAC inhibitors to be tested in
patients

Valporic acid
› a histone deacetylase inhibitor (HDACI), in vitro
induces differentiation of promyelocyte leukemia cell
and proliferation arrest and apoptosis of various
leukemia cell lines.

First compound to be identified as HDAC
inhibitors
 suberoyl anilide hydroxamic acid (SAHA)
 helped define the model pharmacophore for
HDAC inhibitors
Hydroxamic acid
 Reversible inhibitor of Histone deacetylase
 Induce cell cycle arrest at G1, apoptosis, and
cellular differentiation
 Has some uses as anti-cancer drug


Apicidin
 Ethyl ketone component

Depsipeptide
 Modulate the expression of genes

Trapoxin

Two drugs undergoing clinical trial
› MS-275
 A substance that is being studied in the treatment
of cancers of the blood
 Mice experiment and result
› CI-994
 Mechanism of antitumor activity unclear
 Causes accumulation of acetylated histones
although is not able to inhibit HDAC activity in a
direct fashion
www.ifom-ieo-campus.it/research/chiocca.php

HDAC inhibitors induce growth arrest,
differentiation, and/or apoptotic cell death in
transformed cells.

This inhibition of HDAC activity leads to
relaxation of the structure of chromatin.
› The relaxed chromatin structure allows these genes to be expressed,
which finally inhibit tumor cell growth.

Research shows that HDAC inhibitors are well
tolerated can inhibit activity in tumoral cells and
have efficiency in tumor regression.

Further clinical studies are needed to define the optimal
dosage and duration of therapy with HDAC inhibitors in
the fight against cancer.

Additionally, more work is needed to understand the
molecular basis of the HDAC inhibitors selectivity in the
alteration of gene transcription, and in chromatin
dynamics during malignant transformation.

Lastly, the resistance of normal cells to HDAC inhibition
by these agents is also needed to be studied further.
1.
Kouraklis, Author's first name initialG., & Theocharis, S. (2002). Histone Deacetylase Inhibitors
and Anticancer Therapy. Curr. Med Chem - Anti-Cancer Agents. 2, 477-484.
2.
Fang, J (2005).Histone deacetylase inhibitors, anticancerous mechanism and therapy for
gastrointestinal cancers. Journal of Gastroenterology and Hepatology. 20, 988-994.
3.
Miller, T., Witter, D., & Belvedere, S. (2003). Histone Deacetylase Inhibitors. Journal of Medicinal
Chemistry. 46, 5097-5116.
4.
http://www.nlm.nih.gov/medlineplus.html
5.
Bieliauskas, A., Weerasinghe, S., & Pflum, M. (2007). Structural requirements of HDAC
inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid. Bioorganic &
Medicinal Chemistry Letters. 17, 2216-2219.
6.
Campbell, N., & Reece, J. (2002). Biology.San Francisco: Benjamin Cummings.
7.
www.metahistory.org/images/Nucleosome.jpg