Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds. Issue 18 (15th September 2016)

• Record Type: Journal Article
• Authors: Zhou, Hao; Che, Xin; Bao, Guochen; Wang, Na; Peng, Li; Barnash, Kimberly D.; Frye, Stephen V.; James, Lindsey I.; Bai, Xu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 18(2016)
• Page Start: 4436
• Page End: 4440
• Publication Date: 2016-09-15
• Subjects: Cyclic fused and spirocyclic amines -- Histone methyltransferases -- Cross-screening -- Structure based design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.08.004
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 andUNC926, 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 ofUNC669 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. Compound13 was discovered as a novel scaffold that interacts with SETD8 and could serve as a starting point for the future development of PKMT inhibitors.