Abstract
Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays.
Highlights
Epigenetic modifications describe post-translational modifications that occur on the protein without lasting impact on the base genomic code
Initial tests designed around assessing whether a synergistic effect would be observed in real when a combination of G9a inhibitor and histone deacetylases (HDACs) inhibitor used in conjunction
Considering the inherent deficiency of HDACIs as a monotherapy, in conjunction with the past success of incorporating the HDAC pharmacophore into many dual inhibitors, we hypothesized that the core metal ion binding hydrophilic segment could be coupled with the lipophilic core of G9a inhibitors to increase the effectiveness
Summary
Epigenetic modifications describe post-translational modifications that occur on the protein without lasting impact on the base genomic code. Epigenetic modifications are reversible due to the manner in which they occur, making restoration of the epigenome to its normal function a crucial target in many disease models [1,2,3,4,5]. Epigenetics is still a field much in its infancy considering the number of epigenetic targets [5, 6, 9, 10]. From this vast pool, epigenetic markers that related to leukemogenesis and tumorigenesis has shown to be a promising application of epigenetics
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