Identification of novel FLT3 kinase inhibitors

Daphnie Pauwels; Hugo Klaassen; Idoya Lahortiga; Amuri Kilonda; Kris Jacobs; Bram Sweron; Romuald Corbau; Patrick Chaltin; Arnaud Marchand; Jan Cools

doi:10.1016/j.ejmech.2013.03.024

Identification of novel FLT3 kinase inhibitors

Eur J Med Chem. 2013 May:63:713-21. doi: 10.1016/j.ejmech.2013.03.024. Epub 2013 Mar 21.

Authors

Daphnie Pauwels¹, Hugo Klaassen, Idoya Lahortiga, Amuri Kilonda, Kris Jacobs, Bram Sweron, Romuald Corbau, Patrick Chaltin, Arnaud Marchand, Jan Cools

Affiliation

¹ Center for the Biology of Disease, VIB, Leuven 3000, Belgium.

PMID: 23567961
DOI: 10.1016/j.ejmech.2013.03.024

Abstract

FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Blotting, Western
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Hypereosinophilic Syndrome / metabolism
Hypereosinophilic Syndrome / pathology
Leukemia, Monocytic, Acute / metabolism
Leukemia, Monocytic, Acute / pathology
Molecular Structure
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor alpha / metabolism
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor beta / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Protein Kinase Inhibitors
Small Molecule Libraries
FLT3 protein, human
Receptor, Platelet-Derived Growth Factor alpha
Receptor, Platelet-Derived Growth Factor beta
fms-Like Tyrosine Kinase 3