Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.

Epigenetic alterations relate to various human diseases, and developing inhibitors of Kme regulatory proteins is considered to be a new frontier for drug discovery. We were inspired by the known multicyclic ligands, UNC669 and UNC926, which are the first reported small molecule ligands for a methyl-lysine binding domain. We hypothesized that reducing the conformational flexibility of the key amine moiety of UNC669 would result in a unique set of ligands. Twenty-five novel compounds containing a fused bi- or tricyclic amine or a spirocyclic amine were designed and synthesized. To gauge the potential of these amine-containing compounds to interact with Kme regulatory proteins, the compounds were screened against a panel of 24 protein methyltransferases. Compound 13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors

Lysine methyltransferases and their inhibitors

Since 2000, the histone methyltransferases that catalyze the methylation of a number of histone and nonhistone substrates have been discovered. A growing body of literature is indicating that lysine methyltransferases (KMTs) play a crucial role for transcriptional regulation and are involved in cancer and. various other human diseases, thus being of high interest as potential therapeutic targets. In this book chapter, we highlight the discovery, characterization, and application of selective KMT inhibitors, useful for dissecting their physiological functions as well as their disease implications. Over the past decade, there has been an impressive progress regarding the KMT inhibitor discovery, especially conjugating the research interest with the available and novel techniques including new assay methods, high-throughput screening structural biology, and medicinal chemistry approaches. Our goal is to point out herein key advances, challenges, possible future opportunities, and directions, regarding KMT modulation in a preclinical and clinical setting

Methyl-Readers and Inhibitors

Due to their prevalent role in epigenetic gene regulation, methyllysine and methylarginine domain readers have emerged as potential drug targets for small-molecule intervention. Within this book chapter, the biological role and the associated development of potent small molecules inhibiting the protein-protein interaction of methyllysine readers (Tudor, malignant brain tumor, chromo-, and PHD domain) will be discussed. The druggability of these readers and thus their potential to serve as targets for small-molecule ligands will be evaluated critically. Those domains (PWWP, WD40, ankyrin repeats, and ADD domains) which are not yet targeted will be evaluated for their biological actions and eventual therapeutic implications. To sum up, a comprehensive review of the state of the art for all relevant methyl-readers and their inhibitors if present will be given from a medicinal chemistry standpoint of view