Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases.
Eur J Med Chem
; 184: 111710, 2019 Dec 15.
Article
in En
| MEDLINE
| ID: mdl-31614258
ABSTRACT
Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20-30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeutics in relapsing and refractory AML disease harboring various ITD and tyrosine kinase domain mutations, by their ability to overcome drug resistance.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Leukemia, Myeloid, Acute
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Protein Kinase Inhibitors
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Fms-Like Tyrosine Kinase 3
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Drug Discovery
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2019
Document type:
Article
Affiliation country: