1. Afsha Rais

2.  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

4.  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

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

6. The main pharmacological application for HDAC inhibitors is the treatment of cancer.

7.  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

8.  Histone acetylation – attachment of acetyl groups (-COCH 3 ) 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.

9. HDAC Classes Class I HDAC -1, -2, -3, -8 Class IIClass IIa HDAC -4, -5, -7, -9 Class IIbHDAC -6, -10Class III SIRT -1, -2, -3, -4, -5, -6, -7 Class IVHDAC 11

10.  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 › Benzamides

11.  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.

13.  First compound to be identified as HDAC inhibitors  suberoyl anilide hydroxamic acid (SAHA)  helped define the model pharmacophore for HDAC inhibitors

16.  Hydroxamic acid  Reversible inhibitor of Histone deacetylase  Induce cell cycle arrest at G1, apoptosis, and cellular differentiation  Has some uses as anti-cancer drug

17.  Apicidin  Ethyl ketone component  Depsipeptide  Modulate the expression of genes  Trapoxin

18.  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

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

20.  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.

21.  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.

22. 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 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 www.metahistory.org/images/Nucleosome.jpg