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

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

doi:https://dx.doi.org/10.1021/acs.jmedchem.7b01529

Number of the records: 1

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

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SYSNO ASEP	0490059
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	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
Author(s)	Gucký, T. (CZ) Řezníčková, Eva (UEB-Q)_{RID, ORCID} Radošová Muchová, T. (CZ) Jorda, Radek (UEB-Q)_{ORCID, RID} Klejová, Z. (CZ) Malínková, V. (CZ) Berka, K. (CZ) Bazgier, V. (CZ) Ajani, Haresh (UOCHB-X)_{ORCID, RID} Lepšík, Martin (UOCHB-X)_{RID, ORCID} Divoký, V. (CZ) Kryštof, Vladimír (UEB-Q)_{RID, ORCID}
Number of authors	12
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 61, č. 9 (2018), s. 3855-3869
Number of pages	15 s.
Language	eng - English
Country	US - United States
Keywords	INTERNAL TANDEM DUPLICATION ; AMG 925 ; QUIZARTINIB
Subject RIV	EB - Genetics ; Molecular Biology
OECD category	Hematology
R&D Projects	LO1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	LM2015047 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UEB-Q - RVO:61389030 ; UOCHB-X - RVO:61388963
UT WOS	000432204800007
EID SCOPUS	85046415810
DOI	10.1021/acs.jmedchem.7b01529
Annotation	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.
Workplace	Institute of Experimental Botany
Contact	David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469
Year of Publishing	2019

Number of the records: 1