2. Academic Validation
  3. 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

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

  • J Med Chem. 2018 May 10;61(9):3855-3869. doi: 10.1021/acs.jmedchem.7b01529.
Tomáš Gucký 1,  Eva Řezníčková 2,  Tereza Radošová Muchová 3,  Radek Jorda 2,  Zuzana Klejová 3,  Veronika Malínková 1,  Karel Berka 4,  Václav Bazgier 4,  Haresh Ajani 4 5,  Martin Lepšík 5,  Vladimír Divoký 3,  Vladimír Kryštof 2
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science , Palacký University , Šlechtitelů 27 , 783 71 Olomouc , Czech Republic.
  • 2 Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research , Palacký University and Institute of Experimental Botany AS CR , Šlechtitelů 27 , 783 71 Olomouc , Czech Republic.
  • 3 Department of Biology, Faculty of Medicine and Dentistry , Palacký University , Hněvotínská 3 , 775 15 Olomouc , Czech Republic.
  • 4 Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science , Palacky University , 17. listopadu 12 , 771 46 Olomouc , Czech Republic.
  • 5 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences , Flemingovo nám. 2 , 166 10 Prague 6 , Czech Republic.
PMID: 29672049 DOI: 10.1021/acs.jmedchem.7b01529
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.

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