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. Summary of the major classes of
Epigenetic target
Pope, Andrew J., and M. Amy. "are we hitting the mark?." Drug Discovery(2012): 47.
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.
6. 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
14. 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
15. • 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
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.