Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 9, Pages 3855-3869Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01529
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Funding
- Ministry of Education, Youth and Sports of the Czech Republic (National Program of Sustainability I) [L01204]
- Large Infrastructures for Research, Experimental Development and Innovations (IT4Innovations National Supercomputing Center) [LM2015070]
- ELIXIR CZ research infrastructure project (MEYS Grant) [LM2015047]
- Ministry of Health of the Czech Republic [15-28951A]
- Palacky University in Olomouc [IGA_PrF_2018_032, IGAPrF_2018_006]
- Czech Academy of Sciences [RVO 61388963]
- European Regional Development Fund [OP RDE CZ.02.1.01/0.0/0.0/16_019/0000729]
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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 STATS phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
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