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Afsha Rais. In chromatins, DNA is wrapped around proteins of which most are histones. Histones...

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Afsha Rais
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Page 1: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

Afsha Rais

Page 2: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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

Page 3: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

                                                                                                                        

Page 4: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory 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

Page 5: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

www.pharmadd.com/.../graphs/HDAC%20Inhib_lg.gif

Page 6: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

The main pharmacological

applicationfor HDAC

inhibitors is the treatment of

cancer.

Page 7: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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

Page 8: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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.

NH

O

H2N

lysine residue in the N-terminaltails of histones

HAT

C SCoA

O

CH3 HSCoA

HDAC NH

O

N

O

H

acetylated lysine residue

HAT = histone acetyltransferase

HDAC = histone deacetylase

H2OC OH

O

CH3

Page 9: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.
Page 10: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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

› BenzamidesC

O

R N

H

OH

a hydroxamic acid(N-hydroxyamide)

Page 11: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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.

Page 12: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.
Page 13: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

First compound to be identified as HDAC inhibitors

suberoyl anilide hydroxamic acid (SAHA)

helped define the model pharmacophore for HDAC inhibitors

Page 14: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.
Page 15: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.
Page 16: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

Hydroxamic acid Reversible inhibitor of Histone

deacetylase Induce cell cycle arrest at G1,

apoptosis, and cellular differentiation

Has some uses as anti-cancer drug

Page 17: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

Apicidin Ethyl ketone component

Depsipeptide Modulate the expression of genes

Trapoxin

Page 18: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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

Page 19: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

www.ifom-ieo-campus.it/research/chiocca.php

Page 20: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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.

Page 21: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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.

Page 22: Afsha Rais.  In chromatins, DNA is wrapped around proteins of which most are histones.  Histones assist in DNA packaging and have a regulatory role.

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


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