Small-molecule ligands of methyl-lysine binding proteins: Optimization of selectivity for L3MBTL3

Lindsey I. James, Victoria K. Korboukh, Liubov Krichevsky, Brandi M. Baughman, J. Martin Herold, Jacqueline L. Norris, Jian Jin, Dmitri B. Kireev, William P. Janzen, Cheryl H. Arrowsmith, Stephen V. Frye

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish
Pages (from-to)7358-7371
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number18
StatePublished - 26 Sep 2013
Externally publishedYes


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