A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia.
Antineoplastic Agents
/ chemical synthesis
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Indoles
/ chemical synthesis
Leukemia, Myeloid, Acute
/ drug therapy
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors
/ chemical synthesis
Structure-Activity Relationship
Tumor Cells, Cultured
fms-Like Tyrosine Kinase 3
/ antagonists & inhibitors
Acute myeloid leukemia
FLT3
FLT3 D835Y
FLT3-ITD
Tyrosine kinase inhibitor
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 May 2020
01 May 2020
Historique:
received:
04
11
2019
revised:
09
03
2020
accepted:
10
03
2020
pubmed:
22
3
2020
medline:
1
12
2020
entrez:
22
3
2020
Statut:
ppublish
Résumé
Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.
Identifiants
pubmed: 32199135
pii: S0223-5234(20)30199-9
doi: 10.1016/j.ejmech.2020.112232
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Indoles
0
Protein Kinase Inhibitors
0
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112232Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mahboobi, Siavosh; Sellmer, Andreas; Pongratz, Herwig; Pilsl, Bernardette; Krämer, Oliver; Beyer, Mandy are also the inventors of this entity: PCT Int. Appl. (2019), WO 2019034538 A1 20190221.