INHIBITORS OF HISTONE DEACETYLASE

by Selleckchem | Jul 13 2012

HDAC INHIBITORS AND EPIGENEITIC VARIATION
Different functions of the cell like apoptosis, cell multiplication and growth is controlled by genes present in cell histone proteins comprise the large portion these genes. These histone proteins act when they are being acetylated. When these histone proteins get deacetylated they trigger apoptosis because translation of vital proteins gets stopped when they are being deacetylated and also binding capability of DNA is increased due its condensation. Studies showed that in neurodegenerative diseases deacetylation process is seemed blocked which ultimately gave rise to unchecked growth of cells which is characteristic of various kinds of carcinomas and malignancies. These findings forced scientists to discover HDAC inhibitors brought into light the process of HDAC inhibition. Quite large number of researchers described in detail the process of inhibition by administering HDAC inhibitors in clinical as well as pre-clinical trials [1]. Different activity estimation assays are present to assess levels of HDACs [2]. These tests can also be carried out in laboratories manually but varieties of kits are also available to perform tests. Nonisotopic assay can also be used to analyze HDAC inhibitors and it is also compatible with microplate reader [3]. Various tests related to compound profiling and robotic screening are also offered [4] and high throughput screening assay is also available and appropriate for analyzing [5].

WELL-KNOWN HDAC INHIBITORS:
After the association of HDAC was recognized with cancer development HDAC inhibitors were discovered long ago, these drugs were shown efficient in therapy of cancers and malignancies [6]. Vorinostat or SAHA, Entinostat, Panobinostat CUDC-101, LBH589, Romidepsin and Belinostat are among the well-known HDAC inhibitors. HDAC inhibitors supplier provide them to anyone who want to buy HDAC inhibitors. Besides their use for cancer therapy these inhibitors are not only used for stability of mood in neurologic or psychiatric patients but also for treatment of epileptic patients. Since these compounds belong to a large group, HDAC antagonist molecules have still gone under detailed study and entered various stages of clinical trials. Small molecule HDAC inhibitors have not only used in various cancers but also for treatment of neurodegenerative diseases [7].

CLINICAL STUDIES OF HISTONE DEACETYLASE INHIBITORS
Panobinostat was administered in patients suffering from T-cell lymphoma during clinical trials of levels I and II and this drug showed promising results [8].The efficacy of Belinostat was assessed in chronic and pleural mesothelioma malignancy where it proved to be outstanding for the treatment [9] however few tolerable side effects were seen. HER2, EGFR and HDACs were seen to be inhibited by the multiple kinase inhibitors CUDC-101 thus supporting it for cancer treatment [10]. Cervical cancer patients were administered with Valproate which was seen to inhibit cell growth and induce apoptosis hence making it a strong HDAC inhibitor [11]. Vorinostat was the first which got approved from FDA for therapy of CTCL patients. For therapy of metastatic lung cancer, Hodgkin’s lymphoma and breast cancer a similar type of inhibitor is being under research.

REFERENCES:
1. Iglesias OM, e.a., Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clinical and Translational Oncology, 2008.
2. Yuan Z, e.a., Histone Deacetylase Activity Assay Methods in Molecular Biology, 2009.
3. Heltweg B, J.M., A Microplate Reader-Based Nonisotopic Histone Deacetylase Activity Assay. Analytical Biochemistry, 2002.
4. Ciossek T, e.a., A homogeneous cellular histone deacetylase assay suitable for compound profiling and robotic screening. Analytical Biochemistry, 2008.
5. Wegener D, e.a., A fluorogenic histone deacetylase assay well suited for high-throughput activity screening. Chem Biol., 2003.
6. Richon VM, a.O.B.J., Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment. Clin. Cancer Res, 2002.
7. Chuang DM, e.a., Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends in Neurosciences, 2009.
8. Prince HM, B.M., Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma. Hematology Meeting Reports, 2009.
9. Ramalingam SS, e.a., Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol., 2009.
10. Lai CJ, e.a., CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity. Cancer Res, 2010.
11. Blanco AC, e.a., Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Molecular Cancer, 2005.

Cat.No.	Product Name	Information
S1047	Vorinostat (SAHA)	Vorinostat (SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification.
S1053	Entinostat (MS-275)	Entinostat (MS-275, SNDX-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10. Entinostat induces autophagy and apoptosis. Phase 3.
S1030	Panobinostat (LBH589)	Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Panobinostat (LBH589) induces autophagy and apoptosis. Panobinostat effectively disrupts HIV latency in vivo. Phase 3.
S1194	CUDC-101	CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1.
S3020	Romidepsin	Romidepsin (FK228, Depsipeptide, FR 901228, NSC 630176) is a potent HDAC1 and HDAC2 inhibitor with IC50 of 36 nM and 47 nM in cell-free assays, respectively. Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells.
S1085	Belinostat	Belinostat is a novel HDAC inhibitor with IC50 of 27 nM in a cell-free assay, with activity demonstrated in cisplatin-resistant tumors. Belinostat (PXD101) induces autophagy.