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HISTONE DEACETYLASE INHIBITORS – TUMORS AND BEYOND

EPIGENETIC MODULATION BY HDAC INHIBITIORS:
Acetylation process of histone proteins performs a major role in various cellular processes for example cellular growth and apoptosis by preventing the transcription of various proteins by the removal of acetyl groups from the histones hence increasing their DNA binding capacity which leads to the formation of a condensed DNA. This strategy goes wrong in case of neurodegenerative diseases and many types of cancers in which any abnormality in this process causes the removal of this block leading to the cells to proliferate in an uncontrolled manner. Then an HDAC inhibitor pathway comes into light and smoothes the progress of HDAC inhibition. The successful revelation of mechanism of HDAC inhibition has led to their extensive use in different clinical and preclinical studies [1]. Various assays for HDACs have been developed that are used for the analysis of HDAC levels [2]. These activity assays for the HDACs can be performed by using different kits or manually in research labs. Researchers can also perform microplate reader compatible nonisotopic assay for HDAC inhibitors [3], the test that is appropriate for robotic screening and compound profiling [4], or a fluorogenic assay suitable for high-throughput screening [5].


FAMOUS HDAC INHIBITORS:
The relation of cancer, tumorigenesis and HDAC was established so many years ago as a result of which different selective HDAC inhibitors were came to light and were found to be a potential therapeutic agent against tumors [6]. The very well-known of all histone deacetylase kinase inhibitors are Vorinostat (SAHA), Panobinostat, Romidepsin, Entinostat, Belinostat, CUDC-101 and LBH589. Researchers can buy Histone deacetylase inhibitors easily from any supplier of HDACi for their use in laboratory and research. Different HDAC inhibitor drugs have found to be in use as mood stabilizes for the patients relating to neurologic and psychiatric problems and also as anti-epileptics. Some HDAC antagonist molecules are now in different stages of production and some are in efficient use in clinics. The small molecule HDAC inhibitors are now in use against different types of cancers due to their anti-tumor activity against them and they are also being used in various neurodegenerative disorders [7].


HISTONE DEACETYLASE INHIBITORS IN CLINICAL TRIALS:
Panabinostat drug was found to be tested in clinical trials phase I and phase II and was found very valuable in with T-cell lymphoma patients [8]. In the same way Belinostat molecule was found to be very efficient in phase II clinical study of patients of advanced malignant pleural mesothelioma [9] hence having tolerable side effects and disease stabilization in a great number of patients. Another inhibitor molecule CUDC-101, a multi kinase inhibitor which affects HDACs, HER2 and EGFR was found to exert a potent antitumor activity in cancerous cells [10]. Valproate is another HDAC inhibitor molecule in clinical trials has found to give remarkable results regarding apoptosis and inhibition of growth in tumors in clinical trials of phase I in patients of cervical cancer [11]. The first approved HDACi by FDA for using against CTCL was Vorinostat. Another one HDAC inhibitor named Entinostat in now under phase II clinical trial on patients of Hodgkin's lymphoma, metastatic lung cancer and advanced form of breast cancer.


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.

 

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1047 Vorinostat (SAHA) Vorinostat (suberoylanilide hydroxamic acid, SAHA, MK0683) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification. (424) (20)
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. (350) (14)
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. (305) (12)
S1085 Belinostat (PXD101) Belinostat (PXD101, NSC726630, PX-105684) 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. (73) (8)
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. (16) (3)

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