Epigenetics and Small Molecule

Xiang FeiBy chempolicy.or.kr

미국 FDA 로부터 허가를 얻은 후성유전학 약물 4 개

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 단계후성유전적인 유전자 변형은 다양한 질병들의 발병 및 진행에 간여한다

Summary of the major classes of Epigenetic target

Pope, Andrew J., and M. Amy. "are we hitting the mark?." Drug Discovery(2012): 47.

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

Epigentic targetSelection of epigenetic genes disrupted in human tumors

Reference 4Cancer epigenetics reaches mainstream oncologyManuel Rodríguez-Paredes& Manel EstellerNature 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

Epigenetic drugs for cancer therapy

Structures of common HDAC inhibitors

Chemical structures of DNMT inhibitors

Histone acetyltransferase inhibitors

Histone N-methyltransferase inhibitors

Lysine specific demethylase

Known PRMT inhibitors and compounds

AMI-1(IC 50= 1.6 uM)screened from 9000 compounds HTShttp://apps.thesgc.org/resources/phylogenetic_trees/ligands.php?target=PRMT1&domain=HMT

• Epigenetic drugs for cancer therapy is hot

• HDAC inhibitor mechanism research based on SAHA

• Other inhibitors still pre clinical or in biological testing stages

ConclusionArea of Pharmacoepigenomic

Potent HDAC inhibitors, demonstrating in vivo antitumor efficacy and are currently undergoing clinical trials

MY FUTURE WORK FOCUS ON MLL1 INHIBITORS

2014-2015

MLL1 hit compound

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