Identification and characterization of the first fragment hits for SETDB1 Tudor domain.
Crystallography, X-Ray
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Histones
/ antagonists & inhibitors
Humans
Models, Molecular
Molecular Structure
Small Molecule Libraries
/ chemical synthesis
Structure-Activity Relationship
Tudor Domain
/ drug effects
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 09 2019
01 09 2019
Historique:
received:
24
05
2019
revised:
03
07
2019
accepted:
10
07
2019
pubmed:
23
7
2019
medline:
23
9
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
SET domain bifurcated protein 1 (SETDB1) is a human histone-lysine methyltransferase which is amplified in human cancers and was shown to be crucial in the growth of non-small and small cell lung carcinoma. In addition to its catalytic domain, SETDB1 harbors a unique tandem tudor domain which recognizes histone sequences containing both methylated and acetylated lysines, and likely contributes to its localization on chromatin. Using X-ray crystallography and NMR spectroscopy fragment screening approaches, we have identified the first small molecule fragment hits that bind to histone peptide binding groove of the Tandem Tudor Domain (TTD) of SETDB1. Herein, we describe the binding modes of these fragments and analogues and the biophysical characterization of key compounds. These confirmed small molecule fragments will inform the development of potent antagonists of SETDB1 interaction with histones.
Identifiants
pubmed: 31327677
pii: S0968-0896(19)30870-3
doi: 10.1016/j.bmc.2019.07.020
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Histones
0
Small Molecule Libraries
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SETDB1 protein, human
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3866-3878Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.