C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.
Cell Line, Tumor
Crystallography, X-Ray
Drug Screening Assays, Antitumor
/ methods
Enzyme Inhibitors
/ chemical synthesis
Humans
Hydrophobic and Hydrophilic Interactions
Jumonji Domain-Containing Histone Demethylases
/ antagonists & inhibitors
Molecular Structure
Protein Binding
Pyridines
/ chemical synthesis
Pyrimidinones
/ chemical synthesis
Structure-Activity Relationship
Histone demethylases
KDM inhibitors
KDM4 subfamily
KDM5 subfamily
Pyridopyrimidinones
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Sep 2019
01 Sep 2019
Historique:
received:
04
01
2019
revised:
14
05
2019
accepted:
14
05
2019
pubmed:
4
6
2019
medline:
26
7
2019
entrez:
4
6
2019
Statut:
ppublish
Résumé
Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.
Identifiants
pubmed: 31158747
pii: S0223-5234(19)30451-9
doi: 10.1016/j.ejmech.2019.05.041
pmc: PMC6580095
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Pyridines
0
Pyrimidinones
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Types de publication
Journal Article
Langues
eng
Pagination
316-337Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
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