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Discovery of N-(4-(6-Acetamidopyrimidin-4-yloxy)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide (CHMFL-FLT3-335) as a Potent FMS-like Tyrosine Kinase 3 Internal Tandem Duplication (FLT3-ITD) Mutant Selective Inhibitor for Acute Myeloid Leukemia.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Jan 24; Vol. 62 (2), pp. 875-892. Date of Electronic Publication: 2019 Jan 08. - Publication Year :
- 2019
-
Abstract
- Most of the current FMS-like tyrosine kinase 3 (FLT3) inhibitors lack selectivity between FLT3 kinase and cKIT kinase as well as the FLT3 wt and internal tandem duplication (ITD) mutants. We report a new compound 27, which displays GI <subscript>50</subscript> values of 30-80 nM against different ITD mutants and achieves selectivity over both FLT3 wt (8-fold) and cKIT kinase in the transformed BaF3 cells (>300-fold). 27 potently inhibits the proliferation of the FLT3-ITD-positive acute myeloid leukemia cancer lines through suppression of the phosphorylation of FLT3 kinase and downstream signaling pathways, induction of apoptosis, and arresting the cell cycle into the G0/G1 phase. 27 also displays potent antiproliferative effect against FLT3-ITD-positive patient primary cells, whereas it does not apparently affect FLT3 wt primary cells. In addition, it also exhibits a good therapeutic window to PBMC compared to PKC412. In the in vivo studies, 27 demonstrates favorable PK profiles and suppresses the tumor growth in the MV4-11 cell inoculated mouse xenograft model.
- Subjects :
- Acetamides pharmacology
Acetamides therapeutic use
Animals
Apoptosis drug effects
Binding Sites
Cell Line, Tumor
Cell Proliferation drug effects
Drug Evaluation, Preclinical
Female
G1 Phase Cell Cycle Checkpoints drug effects
Humans
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute pathology
Mice
Mice, Nude
Molecular Dynamics Simulation
Mutagenesis
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Protein Structure, Tertiary
Signal Transduction drug effects
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 genetics
fms-Like Tyrosine Kinase 3 metabolism
Acetamides chemistry
Protein Kinase Inhibitors chemistry
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30565931
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b01594