Inhibition of Histone Demethylases Offers a Novel and Promising Approach for the Treatment of Cancer and Other Diseases.

Abstract

Cancer and HDME-dependent proliferative diseases Biological Target: Histone demethylases (HDMEs) Summary: The invention in this patent application relates to heterocyclic aromatic compounds represented generally by formula (I), which arecapableofmodulatingtheactivitiesofhistonedemethylases(HDMEs)andmayprovideusefultherapytotreatcancerandother HDME-dependent proliferative diseases. Nuclear DNA is too large to exist as a linear structure; instead, it exists as a condensed, much smaller but more complex and highlyordered structurecalled chromatin. In additiontoDNA,chromatincontainsproteinandRNA. Chromatinis organizedinto smaller repeat units called nucleosomes composed of the DNA wrapped around a spool made of octamer of histones. Covalent chemical derivatizations of the chromatin components can cause changes in the ordered chromatin structure. Many reversible chemicalmodificationsoccuronthechromatincomponentsthatareessentialtothefunctionsofchromatintodetermineregionsof active and silenced transcription. They also have profound effects on the fundamental cellular processes such as differentiation, proliferation, and apoptosis. Chemical modifications such as methylations of DNA and/or histones are part of epigenetic regulations, which include any heritable changes in gene expression other than those mediated at the DNA sequencing level. Histones, the nucleosome core proteins, contain basic amino acid residues such as lysine and arginine. The amino groups on the lysine or arginine residues are subjected to several covalent modifications such as N-methylation, N-acetylation, and N-phosphorylation. These modifications can affect the histone functions based on their nature and location. Histone tails contain numerous lysine sites; a lysine (K) site is identified by its location on a specific histone (H) subunit, for example, H3K4 refers to a lysine residue in the fourth position on histone H3. The methylated sites are further identified by adding me1, me2, or me3 to denote mono-, di-, or trimethyl derivatives. N-Methylations of the histonelysine residues play critical roles in many epigenetic events. The methylation reaction is regulated by histone methyltransferases and functions as a mechanism to regulate DNA transcription. New evidence suggests that site-specific methylations are linked to specific biological processes ranging from transcriptional regulation to epigenetic silencing. Evidence also suggests that histone methylation may provide a stable genomic imprint that may serve to regulate gene expression as well as other epigenetic phenomena. The reverse process, i.e., the demethylation of methylated histones, is regulated by histone demethylases. There are two main classes of histone demethylases: the amine oxidases catalyzed by flavin adenine dinucleotide (FAD) and the dioxygenases catalyzed by Fe(II)/α-ketoglutarate. Studies have shown that methylation and demethylation of a specific H3 lysine residue can be associated with epigenetic marks that define transcriptionally active or inactive chromatin. For example, while methylation of H3K9 is usually associated with epigenetically silenced chromatin, the methylation of H3K4 is associated with transcriptionally active chromatin. Similarly, di- and trimethylation of H3K27 marks are repressive, while the methylation of H3K36 mark is associated with gene activation. Dysregulation of histone methyltransferases and/or demethylases may result in significant changes in histone lysine methylation, which, in turn, may be responsible for the pathogenesis of several diseases including cancer as well as metabolic, inflammatory, neurodegenerative, and cardiovascular diseases. Therefore, selective modulation of aberrant functions of these enzymes may provide an effective treatment for the above diseases.