Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl- N6-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Leukemia, Myeloid, Acute genetics pathology MeSH
- Diamines chemistry metabolism pharmacology MeSH
- Protein Kinase Inhibitors chemistry metabolism pharmacology MeSH
- Protein Conformation MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Drug Discovery * MeSH
- Antineoplastic Agents chemistry metabolism pharmacology MeSH
- Molecular Docking Simulation MeSH
- fms-Like Tyrosine Kinase 3 antagonists & inhibitors chemistry genetics metabolism MeSH
- Structure-Activity Relationship MeSH
- Xenograft Model Antitumor Assays MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Diamines MeSH
- FLT3 protein, human MeSH Browser
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
- fms-Like Tyrosine Kinase 3 MeSH
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
References provided by Crossref.org
Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors
