Epigenetics and small molecule


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Journal club topic, based on report by sycho@krict.re.kr

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  • A) The chemical structures of the major modification of DNA, cytosine methylation. This modification is mediated by a family of DNMTs. B) A schematic representation of the major modifications of the four canonical histones that create the nucleosomaloctamer. The enzymes generating or removing the modifications are shown in the boxes, and their effects are indicated by the arrows. Methylation of lysine residues can be mono, di or tri, but for clarity this has not been shown. Lysine acetylation is removed by HDACs. Unlike the specific nature of demethylase enzymes, most HDACs can remove acetyl groups from any or all accessible histone lysine residues.
  • Numerous compounds have been reported to be effective against cancer cells by inhibiting components of the epigenetic machineries. This figure shows the most important epigenetic drugs classified depending on their particular epigenetic targets.
  • Efficacies of hydroxamate-based vorinostat (also known as SAHA), trichostatin A (TSA), valproic acid, sodium butyrate, 4-phenyl butyrate, and benzamide-based MC275 and compound 106, were empirically demonstrated in disease animal models. MC1568 and tubucin are shown as examples of class-specific and isoform- selective HDAC inhibitors. Sirtuin 1 (SIRT1)-selective activators resveratrol and SIRT1720, SIRT1/2-selective inhibitor sirtinol, and SIRT2-selective inhibitor AGK2 are shown. Animal efficacy of the putative SIRT1 activator resveratrol was assessed and demonstrated in various disease models as described in the main text.
  • SAM, MTA, Sinefungin, AMI-1, AMI-6, AMI-9
  • Epigenetics and small molecule

    1. 1. Epigenetics and Small Molecule Xiang Fei By chempolicy.or.kr
    2. 2. 미국 FDA로부터 허가를 얻은 후성유전학 약물 4개 DNMT (DNA methyltransferase) 저해제 • Vidaza • Decitabine HDAC-3-(histone deacetylase) 저해제 • Vorinostat • Romidepsin (FK-228) Other 저해제 target • Sirt (silent mating type information regulation 2 homolog) • HMT (histone methyltansferase) • PRMT (protein arginine N- methyltransferase) 후성유전학과 관계되는 저분자 화합물들 의 개발 단계 후성유전적인 유전자 변형은 다양한 질병들의 발병 및 진행에 간여한다
    3. 3. Summary of the major classes of Epigenetic target Pope, Andrew J., and M. Amy. "are we hitting the mark?." Drug Discovery(2012): 47.
    4. 4. DNA methylation takes place along the whole genome, and its disruption is a typical hallmark of cancer. (a) In normal cells (top), CpG islands and CpG island shores usually remain unmethylated, allowing gene transcription. Additionally, DNA methylation within the gene bodies avoids spurious transcription initiations. In cancer cells (bottom), by contrast, although both CpG islands and CpG island shores may be strongly methylated, gene bodies lack this modification. As a result, transcription of many genes gets blocked, and aberrant transcription may occur from incorrect transcription start sites (TSSs). (b) In normal cells (top), methylation of repetitive sequences prevents genomic instability and, again, spurious transcription initiations. Moreover, transposable elements cannot be activated in a methylated environment. In cancer cells (bottom), global hypomethylation triggers genomic instability and aberrant transcription initiations. Concomitant activation of transposons may lead to gene disruption. DNA methylation patterns in normal and cancer cells
    5. 5. Epigentic target Selection of epigenetic genes disrupted in human tumors Reference 4 Cancer epigenetics reaches mainstream oncology Manuel Rodríguez-Paredes& Manel Esteller Nature Medicine 330 -339 (2011) doi:10.1038/nm.2305 The figure shows a selection of genes encoding enzymes that add, remove and recognize histone modifications, as well as members of the DNA methylation machinery, whose deregulation is connected to cancer. • CRCs = Chromatin remodeling complexes • Ac = acetylation • Me = methylation
    6. 6. Epigenetic drugs for cancer therapy
    7. 7. Structures of common HDAC inhibitors
    8. 8. Chemical structures of DNMT inhibitors
    9. 9. Histone acetyltransferase inhibitors
    10. 10. Histone N-methyltransferase inhibitors
    11. 11. Lysine specific demethylase
    12. 12. Known PRMT inhibitors and compounds AMI-1(IC 50= 1.6 uM)screened from 9000 compounds HTS http://apps.thesgc.org/resources/phylogenetic_trees/ligands.php?target=PRMT1&domain=HMT
    13. 13. • Epigenetic drugs for cancer therapy is hot • HDAC inhibitor mechanism research based on SAHA • Other inhibitors still pre clinical or in biological testing stages Conclusion Area of Pharmacoepigenomic Potent HDAC inhibitors, demonstrating in vivo antitumor efficacy and are currently undergoing clinical trials
    15. 15. MLL1 hit compound
    16. 16. Design new compounds
    17. 17. Thank you