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ID: ALA4477270

Journal: Bioorg Med Chem Lett

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

Authors: Zhou H, Che X, Bao G, Wang N, Peng L, Barnash KD, Frye SV, James LI, Bai X.

Abstract: 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.

CiteXplore: 27528434

DOI: 10.1016/j.bmcl.2016.08.004