Within cancer cells, alterations in DNA methylation may lead to promoter hypermethylation at CpG islands and then silence tumor suppressor genes. The inhibition of DNA methyltransferase (DNMT) activity can reactivate silenced tumor suppressor genes, which means DNMT inhibitors have become useful tools to revert cancer cells.

Epigenetic modifications such as DNA methylation, histone methylation, and histone acetylation play essential roles in all aspects of biology. Among all the epigenetic events, DNA methylation is among the best-known epigenetic markers and participates in gene expression control.

Currently, two types of DNMT inhibitors have been discovered, namely nucleoside analogs and non-nucleoside inhibitors. Two nucleoside analogs, 5-azacytidine (Vidaza) and 5-aza-2’-deoxycytidine (Decitabine), have been approved by the FDA for treating myelodysplastic syndrome and leukemia. However, these drugs can be incorporated into DNA and cause covalent trapping and the subsequent depletion of DNMTs. Moreover, these drugs are unstable, show low specificity and have significant toxic side-effects. Compared to nucleoside analogs, non-nucleoside inhibitors may provide a safer way to target DNA methylation. Unfortunately, the known non-nucleoside DNMT inhibitors are typically less potent than nucleoside analogs, and show lack of selectivity to DNMT1.

Collaborated with the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (GUCM), Drug Discovery and Design Center, Shanghai Institute of Meteria Medica (SIMM) identified a serial of novel carbazole derivatives that show high inhibitory potency and specificity to DNMT1, by combining docking-based virtual screening, medicinal chemistry synthesis and biochemical analyses. In human colon and pancreatic cancer cell lines, these compounds can increase apoptosis compared with no treatment. Moreover, the structure-activity relationship (SAR) and binding modes of these inhibitors were also analyzed to assist in the future development of more potent and more specific DNMT1 inhibitors.

This study has been published in the Journal of Medicinal Chemistry (J. Med. Chem. 2014, 57, 9028-9041). Subsequently, it was highlighted by SciBX (The Science Business eXchange), a translational science weekly from Nature Publishing Group and BioCentury Publications (SciBX 7(45); doi:10.1038/scibx.2014.1312).

This study was supervised by Dr. LUO Cheng, ZHENG Mingyue from SIMM, and LIU Bo from GUCM. The first authors are three Ph.D. candidates. CHEN Shijie, WANG Yulan from SIMM and ZHOU Wen from GUCM.

This study was sponsored by the National Natural Science Foundation of China and the National Science and Technology Major Project titled “Key New Drug Creation and Manufacturing Program”.

Comment: http://www.nature.com/scibx/journal/v7/n45/full/scibx.2014.1312.html

Original article: http://pubs.acs.org/doi/abs/10.1021/jm501134e

Contact person ( E-mail ): LUO Cheng (cluo@simm.ac.cn)

Source: Shanghai Institute of Meteria Medica,CAS