1456885-52-1Relevant articles and documents
Small-molecule ligands of methyl-lysine binding proteins: Optimization of selectivity for L3MBTL3
James, Lindsey I.,Korboukh, Victoria K.,Krichevsky, Liubov,Baughman, Brandi M.,Herold, J. Martin,Norris, Jacqueline L.,Jin, Jian,Kireev, Dmitri B.,Janzen, William P.,Arrowsmith, Cheryl H.,Frye, Stephen V.
, p. 7358 - 7371 (2013/10/21)
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.
