Plenary Lecture 4



Title: Small molecule epigenetic modulators of gene expression for use in non-cancer diseases.

Professor Patrick M. Woster

Medical University of South Carolina, USA


Lecture Summary: Chromatin modification mediated through post-translational modification (PTM) of histones is a major regulator of eukaryotic gene expression. Histone PTMs include acetylation, phosphorylation, methylation and other modifications that result in a combination of histone marks collectively described as the histone code.1 This combination of chromatin marks at a given promoter determines, in part, whether specific genes are in an open/transcriptionally active conformation or a closed/transcriptionally repressed conformation.1-2 It has been demonstrated that histone methylation is a reversible and highly regulated process.3  Transcriptional control of gene expression mediated by histone lysine methylation/demethylation is now known to be an important mechanism for the epigenetic control of gene expression, and requires three distinct sets of proteins: 1) writers (protein lysine methyl-transferases and protein arginine methyl-transferases), 2) erasers (histone demethylases) and 3) reader proteins. In addition, LSD1 plays a role as a scaffold protein, and is necessary for normal function of various epigenetic complexes. In cancer, excessive demethylation of H3K4me2 by lysine-specific demethylase 1 (LSD1) can lead to aberrant silencing of genes that produce tumor suppressor proteins. This gene silencing can then play a role in the development and progression of cancer. For this reason, LSD1 has become an important target for the design of novel antitumor agents. Importantly, a number of other diseases have been shown to have an epigenetic basis, and thus LSD1 is regarded as an emerging drug target for diseases other than cancer, such as neurological disease, blood disorders, viral infection, diabetes and fibrosis. We have identified multiple series of small molecules and cyclic peptides that act as potent and selective LSD1 inhibitors.4-6 These inhibitors significantly increase H3K4me2 levels, initiate chromatin remodeling and induce the re-expression of silenced genes. We have also demonstrated that these LSD1 inhibitors can disrupt epigenetic complexes at specific gene promoters. Because of their relatively low toxicity, we have explored the use of these molecules in diseases other than cancer, where cytotoxicity is not a desirable endpoint. In this presentation, we will describe the optimization of these new series of LSD1 inhibitors, and present evidence that LSD1 inhibitor-mediated correction of aberrant gene silencing can have therapeutic potential in a variety of disease states.


Acknowledgments: The research described in this presentation was supported by National Institutes of Health grant 7R01 CA149095


References: 1 Jenuwein, T.; Allis, C. D.: Translating the histone code. Science 2001, 293 (5532), 1074-1080.

2.Lachner, M.; O'Sullivan, R. J.; Jenuwein, T.: An epigenetic road map for histone lysine methylation. J Cell Sci 2003, 116 (Pt 11), 2117-2124.

3.Shi, Y.; Lan, F.; Matson, C.; Mulligan, P.; Whetstine, J.; Cole, P.; Casero, R.; Shi, Y.: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119 (7), 941-953.

4.Kumarasinghe, I. R.; Woster, P. M.: Synthesis and Evaluation of Novel Cyclic Peptide Inhibitors of Lysine-Specific Demethylase 1. ACS Med. Chem. Lett. 2014, 5 (1), 29-33.

5.Kutz, C. J.; Holshouser, S. L.; Marrow, E. A.; Woster, P. M.: 3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitors. MedChemComm 2014, 5 (12), 1863-1870.

6.Sharma, S.; Wu, Y.; Steinbergs, N.; Crowley, M.; Hanson, A.; Casero, R. A. J.; Woster, P.: (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J. Med. Chem. 2010, 53 (14), 5197–5212.

7.Pachaiyappan, B.; Woster, P. M.: Design of small molecule epigenetic modulators. Bioorg Med Chem Lett 2014, 24 (1), 21-32.

8.Sharma, S. K.; Hazeldine, S.; Crowley, M. L.; Hanson, A.; Beattie, R.; Varghese, S.; Sennanayake, T. M. D.; Hirata, A.; Hirata, F.; Huang, Y.; Wu, Y.; Steinbergs, N.; Murray-Stewart, T.; Bytheway, I.; Casero, J., R.A.; Woster, P. M.: Polyamine-based small molecule epigenetic modulators. MedChemComm 2012, 3, 14-21.