Design, Synthesis, and Evaluation of a Novel Dual Fms-Like Tyrosine Kinase 3/Stem Cell Factor Receptor (FLT3/c-KIT) Inhibitor for the Treatment of Acute Myelogenous Leukemia

A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading t...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-10, Vol.54 (20), p.7184-7192
Main Authors: Davies, Robert J, Pierce, Albert C, Forster, Cornelia, Grey, Ron, Xu, Jinwang, Arnost, Michael, Choquette, Deborah, Galullo, Vincent, Tian, Shi-Kai, Henkel, Greg, Chen, Guanjing, Heidary, David K, Ma, Joanne, Stuver-Moody, Cameron, Namchuk, Mark
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Drug Design
Drug Screening Assays, Antitumor
fms-Like Tyrosine Kinase 3 - antagonists & inhibitors
Humans
Hydrogen Bonding
Injections, Intravenous
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - pathology
Macaca fascicularis
Mice
Mice, Inbred BALB C
Models, Molecular
Morpholines - chemical synthesis
Morpholines - pharmacokinetics
Morpholines - pharmacology
Protein Binding
Proto-Oncogene Proteins c-kit - antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Triazoles - chemical synthesis
Triazoles - pharmacokinetics
Triazoles - pharmacology
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Summary:A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N 3-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200712h