Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.
CDK8
P-loop flexibility
Selectivity
Type II inhibitors
pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one scaffold
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 2020
01 Sep 2020
Historique:
received:
11
03
2020
revised:
07
05
2020
accepted:
07
05
2020
pubmed:
1
7
2020
medline:
7
4
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
CDK8 is a cyclin-dependent kinase that forms part of the mediator complex, and modulates the transcriptional output from distinct transcription factors involved in oncogenic control. Overexpression of CDK8 has been observed in various cancers, representing a potential target for developing novel CDK8 inhibitors in cancer therapeutics. In the course of our investigations to discover new CDK8 inhibitors, we designed and synthesized tricyclic pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives, by introduction of chemical complexity in the multi-kinase inhibitor Sorafenib taking into account the flexibility of the P-loop motif of CDK8 protein observed after analysis of structural information of co-crystallized CDK8 inhibitors. In vitro evaluation of the inhibitory activity of the prepared compounds against CDK8 led us to identify compound 2 as the most potent inhibitor of the series (IC
Identifiants
pubmed: 32599324
pii: S0223-5234(20)30414-1
doi: 10.1016/j.ejmech.2020.112443
pii:
doi:
Substances chimiques
Oxazepines
0
Protein Kinase Inhibitors
0
Pyridines
0
Sorafenib
9ZOQ3TZI87
CDK8 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 8
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112443Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.