Discovery of N-2-(4-Amino-cyclohexyl)-9-cyclopentyl-N-6-(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations

0490059 - ÚEB 2019 RIV US eng J - Journal Article
Gucký, T. - Řezníčková, Eva - Radošová Muchová, T. - Jorda, Radek - Klejová, Z. - Malínková, V. - Berka, K. - Bazgier, V. - Ajani, Haresh - Lepšík, Martin - Divoký, V. - Kryštof, Vladimír
Discovery of N-2-(4-Amino-cyclohexyl)-9-cyclopentyl-N-6-(4-morpholin-4-ylmethyl-phenyl)-9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations.
Journal of Medicinal Chemistry. Roč. 61, č. 9 (2018), s. 3855-3869. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) LO1204; GA MŠMT(CZ) LM2015047; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61389030 ; RVO:61388963
Keywords : INTERNAL TANDEM DUPLICATION * AMG 925 * QUIZARTINIB
OECD category: Hematology; Medicinal chemistry (UOCHB-X)
Impact factor: 6.054, year: 2018

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.
Permanent Link: http://hdl.handle.net/11104/0284356