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Bioorg Med Chem. 2014 Apr 1;22(7):2253-60. doi: 10.1016/j.bmc.2014.02.024. Epub 2014 Feb 28.

Using 'biased-privileged' scaffolds to identify lysine methyltransferase inhibitors.

Author information

1
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.
2
Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA.
3
Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: kapoor@rockefeller.edu.

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.

KEYWORDS:

Inhibitors; KMTases; Post-translational modifications; SET7; ‘Privileged’ scaffolds

PMID:
24650704
PMCID:
PMC4038709
DOI:
10.1016/j.bmc.2014.02.024
[Indexed for MEDLINE]
Free PMC Article

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