Histone methyltransferase inhibitors

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

---

Heinke, R., Spannhoff A., Huda, E., Meier, R., Jung, M. and Sippl, W. (2009) Virtual screening and biological characterization of histone methyltransferase inhibitors PRMTl. ChemMedChem, 4, 69-77. 

Although the field of histone methyltransferase inhibitors is still in its infancy in terms of drug discovery, a lot of kno vledge in terms of their biological roles has been acquired. Test systems for in vitro and in vivo evaluation are available and model approaches have been presented already that led to inhibitors of these enzymes with promising cellular activity. Therefore, a dynamic development of the field can be expected vhich hopefully vill lead to clinical candidates in the upcoming years. 

Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, Koh TL, Yu Q, Chng WJ. 2011. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 118 2830-2839. 

Efforts to identify specific inhibitors of histone methyltransferases are in their early stages, and only two specific KMT inhibitors have been identified. The fungal mycotoxin chaetocin (9, Figure 2) inhibits the KMT Su(var)3-9 from Drosophila with an IC50 of 0.8 iM and produces a... 

Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262 75—83 Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem BioH 143-145 Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276(42) 38837-38843... 

During the past several years, a variety of crystal structures of histone lysine and arginine methyltransferase in complex with the cofactor analog SAH and/or in complex with peptide substrates have been reported [92]. However, no 3D structure of a complex between a histone methyltransferase (HMT) and an inhibitor has been reported so far. Due to the lack of experimental structures, a variety of molecular modeling and docking studies has been carried out for H MTs in order to understand the structural requirements for inhibitor binding. 

Mai, A., Valente, S., Cheng, D., Perrone, A., Ragno, R., Simeoni, S. et al. (2007) Synthesis and biological validation of novel synthetic histone/protein methyltransferase inhibitors. ChemMedChem, 3, 987-991. 

Griffiths, E.A. and Gore, S.D. (2008) DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Seminars in Hematology, 45, 23-30. 

Zhu, W.G. and Otterson, G.A. (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Current Medicinal Chemistry Anticancer Agents, 3, 187-199. 

Spannhoff,A.,Sippl,W.andJung,M.(2008) Cancer treatment of the future inhibitors of histone methyltransferases. The International Journal of Biochemistry ei Cell Biology, 10.1016/j.biocel.2008.1007.1024. 

F (1997) is a potent histone deacetylase inhibitor, and psammaplin G (1998) is a potent DNA methyltransferase inhibitor. A Southern Japanese version of Pseudoceratina purpurea has yielded pseudoceratins A (2002) and B (2003) (1834). 

Figure 2 (A) DNA methyltransferase inhibitors. (B) Representative histone deacety-lase inhibitors. Source From Journal of the National Cancer Institute (89) copyright Oxford University Press, 2003.

One year later, in 2010, Sodeoka et al. reported on the total synthesis of two similar dimeric TDKPs, (+)-chaetocin A (677) and its antipode e /-chaetocin A (678) (424, 425) in only nine steps. The natoral product was isolated from Chaetomium minutum (426) and shows antibacterial and cytostatic activity (427, 428) as well as an inhibitory effect on histone methyltransferases (429). The latter play an important role in gene expression and the total synthesis of inhibitors and their analogs could lead to helpful tools for epigenetic research (Scheme 10.9). 

---