Abstract：
:Activating mutations in FMS-like tyrosine kinase 3 (FLT3) occur in 25% of acute lymphoid and 30% of acute myeloid leukaemia cases. Therefore, FLT3 is a potential therapeutic target for small molecule kinase inhibitors. In this study, protein-ligand interactions between FLT3 and kinase inhibitors (CEP701, PKC412, sunitinib, imatinib and dasatinib) were obtained through homology modelling and molecular docking. A cellular system for experimental testing of the inhibitors was also established by expressing wildtype and internal tandem duplication mutant FLT3 (FLT3-WT and FLT3-ITD) in FDC-P1 cells. Imatinib and dasatinib could not be docked into any of the FLT3 models, consistent with their lack of activity in the experimental assays. CEP701, PKC412 and sunitinib interacted with the ATP-binding pocket of FLT3, forming H-bonds with Cys694 and Glu692. Based on the EC50 values in the cell proliferation assay, CEP701 was the most potent inhibitor; sunitinib and PKC412 were ranked second and third, respectively. Sunitinib was the most selective inhibitor, followed by PKC421 and CEP701. The potency of sunitinib and to a lesser extent CEP701 in inhibition of FLT3 autophosphorylation was lower than the cell proliferation inhibition, indicating that inhibition of FLT3 downstream proteins may contribute to the cellular effects. It was shown in this study that the docking procedure was able to differentiate FLT3 inhibitors from ineffective compounds. Additionally, interaction with the phosphate binding region in the ATP-binding pocket increased potency at the cost of selectivity. These findings can be applied in designing highly effective and selective inhibitors for FLT3 and other related kinases.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Mashkani B,Tanipour MH,Saadatmandzadeh M,Ashman LK,Griffith Rdoi
10.1016/j.ejphar.2016.02.048subject
Has Abstractpub_date
2016-04-05 00:00:00pages
156-66eissn
0014-2999issn
1879-0712pii
S0014-2999(16)30072-3journal_volume
776pub_type
杂志文章abstract：:The existence of neurogenic mediator candidates apart from noradrenaline and acetylcholine involved in the control of vascular tone has attracted enormous attention during the past few decades. One such mediator is neuropeptide Y (NPY), which is co-localized with noradrenaline in sympathetic perivascular nerves. Stimu...
journal_title：European journal of pharmacology
pub_type： 杂志文章,评审
doi：10.1016/s0014-2999(98)00242-8
更新日期：1998-05-15 00:00:00
abstract：:Alzheimer's disease (AD) is a chronic neurodegenerative disorder that leads to disturbances of cognitive functions. Although the primary cause of AD remains unclear, brain acetylcholine deficiency, oxidative stress and neuroinflammation may be considered the principal pathogenic factors. The present study was construc...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2013.11.008
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abstract：:The effects of indapamide on contractile responses in various isolated artery rings and on spontaneous mechanical activity in portal vein segments were investigated. Arteries used were: rabbit aorta, mesenteric (fifth branch), femoral and basilar, and sheep coronary arteries. 45Ca2+ uptake was also analysed in rabbit ...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(93)90630-z
更新日期：1993-11-30 00:00:00
abstract：:The efficacy of SR 47436 (BMS-186295), 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)- biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, a non-peptide angiotensin AT1 receptor antagonist, was characterized in various conscious hypertensive rat models. In spontaneously hypertensive rats, single intravenous or oral doses o...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(94)00484-6
更新日期：1994-11-03 00:00:00
abstract：:The relation of the structure of 31 quaternary ammonium compounds (28 inhibitors; 3 substrate analogues) with their effects on the activity of acetylcholinesterase (EC 3.1.1.7; AChE) was studied. The compounds were structurally related to the natural substrate acetylcholine (ACh). All bear a trimethylammonium moiety a...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0922-4106(89)90007-2
更新日期：1989-05-11 00:00:00
abstract：:Rings of canine bronchi were suspended for isometric tension recording. Contractions produced by exogenously added acetylcholine were inhibited by pirenzepine and pancuronium. The pKB values were 6.76 for pirenzepine (calculated at 10(-6) M) and 5.30 and 5.13 for pancuronium (calculated at 10(-5) and 3 X 10(-5) M, res...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(87)90643-1
更新日期：1987-08-04 00:00:00
abstract：:Osteoporosis is a high mortality and morbidity ranged skeletal disease and results in high costs of medical care in the European Union. We evaluated the possible protective effect of alpha-lipoic acid (ALA) on rat bone metabolism in ovariectomy and inflammation-mediated osteoporosis models. Groups were designed as: (1...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2013.07.033
更新日期：2013-10-15 00:00:00
abstract：:The formation of epidural fibrosis adjacent to the dura mater is a complex multi-step process that is associated with a marked reduction in tissue cellularity and the excessive deposition of extracellular matrix components. Extensive epidural fibrosis is a major cause of post-laminectomy syndrome. Decorin strongly inh...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2013.12.017
更新日期：2014-02-05 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(94)90409-x
更新日期：1994-01-14 00:00:00
abstract：:Transfected Chinese hamster ovary cells expressing human alpha2A-, alpha2B- and alpha2C-adrenoceptor subtypes were used to monitor alpha2-adrenoceptor-stimulated GTP hydrolysis. Incubation with 100 microM (-)-adrenaline resulted in stimulation of pertussis toxin-sensitive GTPase by 380% after activation of the alpha2A...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(99)00306-4
更新日期：1999-06-11 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2016.11.041
更新日期：2017-01-05 00:00:00
abstract：:The earliest hallmarks of sporadic Alzheimer's disease (sAD) are impaired glucose metabolism, chronic neuroinflammation, diminished synaptic plasticity and subsequent cognitive decline. The safest antidiabetic drug metformin has shown both glucose metabolism-improving and cognition-enhancing action in type 2 diabetes ...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2020.173290
更新日期：2020-08-15 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(82)90239-4
更新日期：1982-02-26 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0922-4106(90)90010-u
更新日期：1990-04-25 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(98)00028-4
更新日期：1998-03-26 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(80)90458-6
更新日期：1980-09-05 00:00:00
abstract：:Systemic or intracerebral administration of kainic acid in rodents induces neuronal death followed by a cascade of neuroplastic changes in the hippocampus. Kainic acid-induced neuroplasticity is evidenced by alterations in hippocampal neurogenesis, dispersion of the granule cell layer and re-organisation of mossy fibr...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2011.05.008
更新日期：2011-09-01 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
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abstract：:In a recent study we have shown that it was possible to recognize and record two independent behavioural patterns elicited by apomorphine (s.c.): one behaviour characterized by increased locomotion, sniffing and repetitive head and limb movements and another, characterized by compulsive gnawing. In the present study w...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(77)90250-3
更新日期：1977-11-15 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2014.05.033
更新日期：2014-09-05 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(97)01192-8
更新日期：1997-09-10 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2009.04.050
更新日期：2009-08-01 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(77)90296-5
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2012.11.058
更新日期：2013-02-15 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/j.ejphar.2009.03.050
更新日期：2009-06-02 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(88)90333-0
更新日期：1988-11-01 00:00:00
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journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/0014-2999(91)90490-h
更新日期：1991-07-09 00:00:00
abstract：:The influence of enzymatic degradation on the neurotransmitter actions of ATP was studied using the ecto-ATPase inhibitor 6-N,N-diethyl-D-beta,gamma-dibromomethyleneATP (ARL 67156). Field stimulation of the parasympathetic nerves innervating guinea-pig urinary bladder muscle strips (1-8 Hz for 20 s) produced character...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：
更新日期：1997-06-25 00:00:00
abstract：:The present study was undertaken to investigate the effects of intracavernosal injections of adrenomedullin, a novel hypotensive peptide, on penile erection in anesthetized cats. Responses to adrenomedullin were compared to those elicited by intracavernosal injection of the control triple-drug combination (1.65 mg pap...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(96)00924-7
更新日期：1997-01-14 00:00:00
abstract：:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare monogenic idiopathic partial epilepsy characterized by clusters of frontal lobe motor seizures during sleep. Recently, it has been shown that mutations of the chromosome-20q-located neuronal nicotinic acetylcholine receptor alpha4-subunit (CHRNA4) a...
journal_title：European journal of pharmacology
pub_type： 杂志文章
doi：10.1016/s0014-2999(00)00065-0
更新日期：2000-03-30 00:00:00
