Institute of Microbial Technology (सूक्ष्मजीव प्रौद्योगिकी संस्थान)  
A Council of Scientific & Industrial Research (वैज्ञानिक औद्योगिक अनुसंधान परिषद)
 
 
EpiDBase
Small molecule modulators of Epigenetic proteins
 
 
  The term “Epigenetics” was first introduced by C. H. Waddington in 1942 (1). Waddington defined Epigenetics as “the causal interactions between genes and their products, which bring the phenotype into being”, and it was in reference to the embryonic development (1). Epigentics provides a parallel universe, where the heritable changes result in differential gene expression independent of DNA sequence. Epigenetic changes are modulated by three important protein families: writers, erasers and readers (2-4). These changes cause the activation and deactivation of genetic code for transcription and modulate expression levels, which has implications in various diseases like cancer, diabetes, neurodegenerative and cardiovascular disorders. Epigenetic changes are controlled to a great extent by environmental factors and diet (5). Epigenetics is dynamic in nature, suggesting that it is possible to alter the epigenetic states by manipulating the epigenetic factors. With development of clinically approved inhibitors of DNA methylation and histone deacetylase (HDAC), it has been proved that these proteins are pharmacologically important targets (6). Further role of epigenetic proteins like sirtuins in cancer, neurodegenerative and metabolic diseases is leading to development of new activators for this class of proteins (6-10). Epigenetic proteins are emerging as an exciting platform for drug discovery. Recent years have witnessed a huge progress in the understanding of these epigenetic modulators and their significance as targets for drug discovery. Many small molecules have been reported in literature, which target these protein families (11, 12). The small molecule inhibitors of DNMT1 such as RG108, psammaplin A and EGCG are in preclinical trials. Many of HDAC class I and II inhibitors such as sodium butyrate, valporic acid, trichostatin A, belinostat, LAQ824, panobinostat, scriptaid, trapoxin, apicidin, CHAP1, MS275, MGCD101 are under clinical trials. SAHA and romidepsin (HDAC inhibitors) had been approved by FDA for cutaneous T-cell lymphoma (13, 14). The sirtuin modulators such as resveratrol, splitomycin, sirtinol, SRT1720, EX527, cambinol, suramin have been extensively studied and are promising candidates. Inhibitors of other epigenetic protein families such as HATs and HMTs are also been explored. Some of well known inhibitors of HATs are LysCoA, anacardic acid, garcinol and curcumin. Similarly AMI-1, AMI-5, chaetocin are well studied inhibitors of HMT protein families. Targeting various epigenetic protein families is an active research area. There is a need of common platform of known epigenetic protein modulators to facilitate the design and synthesis of small molecule therapeutics for epigenetic drug discovery. This motivated us to come up with a database which would serve as a platform for all experimentally validated small molecules showing interaction with epigenetic protein families. EpiDBase offers interactive analysis of small molecules which modulates various epigenetic protein families. Currently EpiDBase has 11422 entries comprising of 5784 unique molecules associated with 220 protein families. EpiDBase also offers substructure and similarity based search analysis. We have also provided three-dimensional analysis of various small molecules embedded in the EpiDBase. We believe this database will be of immense use in developing new drugs targeting various epigenetic protein families.  
 
  References
 
  1. Waddington, CH (1942). Endeavour 1, 18-20
  2. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11: 384-400.
  3. Musselman CA, Lalonde ME, Cote J, Kutateladze TG (2012) Perceiving the epigenetic landscape through histone readers. Nature Structural & Molecular Biology 19: 1218-1227.
  4. Dawson MA, Kouzarides T and Huntly BJP (2012) Targeting Epigenetic Readers in Cancer. New Engl J Med 367, 647-657.
  5. Feil R and Fraga MF (2011) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13: 97-109.
  6. Taberlay, P. C., Jones, P. A (2011) DNA methylation and cancer. Prog Drug Res 67, 1–23.
  7. Kalebic T (2003) Epigenetic changes: Potential therapeutic targets. Ann Ny Acad Sci 983: 278-285.
  8. Szyf M (2007) The dynamic epigenome and its implications in toxicology. Toxicol Sci 100: 7-23.
  9. Pei L, Choi JH, Liu J, Lee EJ, McCarthy B, Wilson JM, Speir E, Awan F, Tae H, Arthur G, Schnabel JL, Taylor KH, Wang X, Xu D, Ding HF, Munn DH, Caldwell C, Shi H (2012) Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia. Epigenetics 7: 567-578.
  10. Lahue RS and Frizzell A (2012) Histone deacetylase complexes as caretakers of genome stability. Epigenetics 7: 806-810.
  11. Rosse G (2012) Novel and Selective Inhibitors of Histone Deacetylase. Acs Med Chem Lett 3: 879-880.
  12. Jia H, Kast RJ, Steffan JS, Thomas EA (2012) Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Human Molecular Genetics 21: 5280-5293.
  13. Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R (2007) FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist12:1247-52.
  14. VanderMolen KM, McCulloch W, Pearce CJ, Oberlies NH (2011) Romidepsin (Istodax, NSC 630176, FR901228, FK228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. J Antibiot 64:525-31.
 
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