title: Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3.
abstract: Lysine methylation is a key epigenetic mark, the dysregulation of which is linked to many diseases. Small-molecule antagonism of methyl-lysine (Kme) binding proteins that recognize such epigenetic marks can improve our understanding of these regulatory mechanisms and potentially validate Kme binding proteins as drug-discovery targets. We previously reported the discovery of 1 (UNC1215), the first potent and selective small-molecule chemical probe of a methyl-lysine reader protein, L3MBTL3, which antagonizes the mono- and dimethyl-lysine reading function of L3MBTL3. The design, synthesis, and structure-activity relationship studies that led to the discovery of 1 are described herein. These efforts established the requirements for potent L3MBTL3 binding and enabled the design of novel antagonists, such as compound 2 (UNC1679), that maintain in vitro and cellular potency with improved selectivity against other MBT-containing proteins. The antagonists described were also found to effectively interact with unlabeled endogenous L3MBTL3 in cells.
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 at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Lindsey I
authors.initials: LI
authors.lastname: James
authors.forename: Victoria K
authors.initials: VK
authors.lastname: Korboukh
authors.forename: Liubov
authors.initials: L
authors.lastname: Krichevsky
authors.forename: Brandi M
authors.initials: BM
authors.lastname: Baughman
authors.forename: J Martin
authors.initials: JM
authors.lastname: Herold
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Norris
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kireev
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
mesh_terms: D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008239:Lysine / Q000378:metabolism*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004268:DNA-Binding Proteins; C502190:L3MBTL3 protein, human; D008024:Ligands; D054852:Small Molecule Libraries; D008239:Lysine
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