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.

Abstract

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.

• Authors: Tomáš Gucký, Eva Řezníčková, Tereza Radošová Muchová, Radek Jorda, Zuzana Klejová, Veronika Malínková, Karel Berka, Václav Bazgier, Haresh Ajani, Martin Lepšík, Vladimír Divoký, Vladimír Kryštof
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 9 Pg. 3855-3869 (05 10 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29672049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Diamines
• Protein Kinase Inhibitors
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Cell Line, Tumor
• Diamines (chemistry, metabolism, pharmacology)
• Drug Discovery
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mice
• Molecular Docking Simulation
• Protein Conformation
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, chemistry, genetics, metabolism)