The Design and Development of Polyamine-Based Analogs with Epigenetic Targets

The natural polyamines are polycationic alkylamines with multiple functions that are essential for cell growth. The association between polyamines and chromatin extends to DNA–protein interaction, particularly those interactions involving histone modifications and chromatin remodeling. The increasing knowledge of the unique role that the polyamines play in chromatin regulation has received considerable attention in recent years and led to our interest in exploiting structure-specific polyamine analogs in targeting chromatin remodeling enzymes for cancer therapy. We first designed and synthesized a series of polyaminohydroxamic acid and polyaminobenzamide compounds using various polyamine analog backbone structures combined with active site-directed inhibitor moieties of the class I/II histone deacetylases (HDACs). We then demonstrated that specific members of these analog families functionally inhibit activity of histone deacetylases and re-activate tumor-suppressor genes in cancer cells. The recent identification of flavin-dependent histone lysine-specific demethylase 1 (LSD1) demonstrated that histone methylation is a dynamic process similar to other post-translational histone modifications. LSD1 has been identified as a component of transcriptional repressor complexes that specifically catalyzes demethylation of mono- and dimethyl-lysine 4 of histone 3, key positive chromatin marks associated with transcriptional activation. Aberrant demethylation of lysine 4 of histone 3 by LSD1 may broadly repress the expression of tumor suppressor genes that are important in human cancers. Based on the structural and catalytic similarities of LSD1 and polyamine oxidases, we recently identified a group of biguanide, bisguanidine and oligoamine polyamine analogs as potent inhibitors of LSD1. Treatment with these LSD1 inhibitors leads to re-expression of aberrantly silenced genes in cancer cells. The results from these studies imply that the use of these novel polyamine-based HDAC and LSD1 inhibitors may represent a new direction for epigenetic drug development in cancer prevention and therapy.