title: Design, synthesis, and protein methyltransferase activity of a unique set of constrained amine containing compounds.
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.
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Che
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China.
authors.forename: Guochen
authors.initials: G
authors.lastname: Bao
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Barnash
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.affiliation: Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: ingerman@email.unc.edu.
authors.forename: Lindsey I
authors.initials: LI
authors.lastname: James
authors.affiliation: The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Changchun, Jilin 130021, PR China. Electronic address: xbai@jlu.edu.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Bai
mesh_terms: D000588:Amines / Q000737:chemistry*; D015195:Drug Design; D008780:Methyltransferases / Q000378:metabolism*
chemical_list: D000588:Amines; D008780:Methyltransferases
keywords: Cross-screening; Cyclic fused and spirocyclic amines; Histone methyltransferases; Structure based design