title: Using 'biased-privileged' scaffolds to identify lysine methyltransferase inhibitors.
abstract: Methylation of histones by lysine methyltransferases (KMTases) plays important roles in regulating chromatin function. It is also now clear that improper KMTases activity is linked to human diseases, such as cancer. We report an approach that employs drug-like 'privileged' scaffolds biased with motifs present in S-adenosyl methionine, the cofactor used by KMTases, to efficiently generate inhibitors for Set7, a biochemically well-characterized KMTase. Setin-1, the most potent inhibitor of Set7 we have developed also inhibits the KMTase G9a. Together these data suggest that these inhibitors should provide good starting points to generate useful probes for KMTase biology and guide the design of KMTase inhibitors with drug-like properties.
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA; Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, AP, India. Electronic address: skashyap@iict.res.in.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kashyap
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Sandler
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Peters
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Martinez
authors.affiliation: Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: kapoor@rockefeller.edu.
authors.forename: Tarun M
authors.initials: TM
authors.lastname: Kapoor
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011495:Histone-Lysine N-Methyltransferase
keywords: Inhibitors; KMTases; Post-translational modifications; SET7; ‘Privileged’ scaffolds