Abstract：
:B-Raf kinase is the key point in a main branch of mitogen-activated protein kinase pathways and some of its mutations, such as the V600E mutation, lead to the persistent activation of ERK signaling and the trigger of severe diseases, including melanoma and other somatic cancers. Several potent drugs have been approved to treat B-Raf-related tumors, however, cases of resistance and relapse have been reported universally. Hence, differential scaffolds are in need to alleviate the scarcity of drugs and benefit the therapy of B-Raf-mutant cancers. Herein we report our recent work on the construction of novel B-RafV600E inhibitors employing fragment-based drug design strategy. In this research, we decomposed known inhibitors to fragments and rebuilt new candidates using these blocks according to the evaluation of their potential. Lead compounds were synthesized after selection by means of virtual screening and molecular dynamics validation. Afterwards, we tested the pharmacological efficiency of these entities both in vitro and in vivo utilizing A375 xenograft model. The results favored our rational design intention and hinted this new kind of inhibitors might be helpful in the further explorations of potent agents.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Wang PF,Qiu HY,Wang ZF,Zhang YJ,Wang ZC,Li DD,Zhu HLdoi
10.1016/j.bcp.2017.02.022subject
Has Abstractpub_date
2017-05-15 00:00:00pages
63-76eissn
0006-2952issn
1873-2968pii
S0006-2952(17)30114-4journal_volume
132pub_type
杂志文章abstract：:Two specific binding sites for histamine were characterized in the cell membrane of N-nitroso-N-methylurea (NMU)-induced tumors. The first one, with higher affinity (Kd = 4 +/- 2 nM), was further identified as an H2 type, while the lower affinity one (35 +/- 10 nM) corresponded to an H1 receptor. Histamine concentrati...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(95)00108-c
更新日期：1995-06-29 00:00:00
abstract：:Epidemiological and experimental animal data indicate that exposure to both metals and metalloid species exacerbates the risk of human diseases, particularly cancers. Vascular endothelial growth factor (VEGF), which performs a primary function in both tumor progression and angiogenesis, is up-regulated due to exposure...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2006.03.021
更新日期：2006-06-28 00:00:00
abstract：:The source of urinary catecholamines and the mechanisms by which tyrosine administration raises these compounds were investigated in rats. Adrenalectomy blocked the tyrosine-induced rise in urinary epinephrine but not dopamine or norepinephrine. Following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), the tyr...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(82)90578-0
更新日期：1982-11-15 00:00:00
abstract：:The present study was carried out to analyze the sex differences in the retention of Cd in rats treated with a small amount of Cd, and its mechanisms. Cd and Zn concentrations in the kidney and liver of female rats treated with 28 nmol Cd or 1 nmole Zn were significantly higher than those in male rats. Pretreatment wi...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(88)90305-x
更新日期：1988-08-15 00:00:00
abstract：:It has been hypothesized that oxidative modification of low density lipoprotein plays a key role in the pathogenesis of atherosclerosis. In order to elucidate the role of lipid oxidation and its inhibition in vivo, apolipoprotein E and alpha-tocopherol (alphaT) transfer protein double knockout (ApoE(-/-)alpha-TTP(-/-)...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2007.07.020
更新日期：2007-10-01 00:00:00
abstract：:Endosulfan (E) is an organochloric insecticide, which is quickly metabolized and eliminated from the body system. Toxic effects of E and its metabolites have been reported. The influence of E and its metabolites, viz. endosulfan sulfate (ES), endosulfan diol (ED) and endosulfan lactone (EL), has been examined on rat l...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90112-6
更新日期：1984-11-01 00:00:00
abstract：:The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabol...
journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
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更新日期：2018-08-01 00:00:00
abstract：:Products derived from arachidonic acid (AA) via both the cyclo-oxygenase and lipoxygenase pathways play a role in inflammation: prostaglandins (PGs), particularly PGE2, contribute to the formation of oedema, erythema and hyperalgesia whereas leukotriene B4 (LTB4), a product of the 5' lipoxygenase, may modulate the rec...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90246-7
更新日期：1986-03-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2019.03.019
更新日期：2019-05-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2011.12.003
更新日期：2012-03-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2012.10.024
更新日期：2013-01-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90194-5
更新日期：1994-02-09 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(03)00406-4
更新日期：2003-09-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2015.12.005
更新日期：2016-04-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(00)00445-7
更新日期：2000-11-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(02)01555-1
更新日期：2003-02-15 00:00:00
abstract：:Recent studies in our laboratory have revealed that Mn2+ is capable of promoting cell spreading and neurite outgrowth in PC12 cells, a process which is dependent on Mn2+ stimulation of the interaction between extracellular matrix (ECM) components and their corresponding integrin receptors. Since the major ECM proteins...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90534-7
更新日期：1994-04-29 00:00:00
abstract：:In the present study, a screen of adenosine analogs as potential modulators of arylamine-N-acetyltransferase 1 activity identified ATP as an inhibitor within its range of physiological concentrations. Kinetically, ATP was a non-competitive inhibitor with respect to the acetyl acceptor but a competitive inhibitor with ...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2018.10.013
更新日期：2018-12-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(84)90306-x
更新日期：1984-02-15 00:00:00
abstract：:A series of N-hydroxy-N'-aminoguanidine derivatives was studied for their effects on L1210 cell growth and ribonucleotide reductase activity. With the twelve compounds studied, there was a good correlation between the inhibition of L1210 cell growth and the inhibition of ribonucleotide reductase activity. The most pot...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(85)90561-1
更新日期：1985-08-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(85)90204-7
更新日期：1985-12-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章,评审
doi：10.1016/j.bcp.2007.12.008
更新日期：2008-05-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2016.01.013
更新日期：2016-03-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(98)00285-8
更新日期：1999-01-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90015-9
更新日期：1994-01-20 00:00:00
abstract：:We have studied the effect of nitric oxide (NO) and hydrogen peroxide (H(2)O(2)), two reactive oxygen species (ROS) on histamine release (HR) from RBL-2H3 cells, a rat mucosal-type mast cell line. Marked HR was elicited by antigen (DNP-HSA), calcium ionophore A23187, sodium fluoride or phospholipase C, but not with co...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/s0006-2952(01)00770-5
更新日期：2001-12-01 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(94)90118-x
更新日期：1994-07-19 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(86)90399-0
更新日期：1986-09-15 00:00:00
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journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/j.bcp.2015.08.095
更新日期：2015-11-01 00:00:00
abstract：:This study was designed to examine the relationship between the extent of Sandimmun (cyclosporin A, SIM) metabolism and SIM-induced hepatotoxicity both in vivo and in primary cultures of rat hepatocytes. Firstly, SIM (50 mg/kg p.o.) was administered daily to male Wistar rats for 10 days with or without co-administrati...
journal_title：Biochemical pharmacology
pub_type： 杂志文章
doi：10.1016/0006-2952(90)90024-f
更新日期：1990-01-15 00:00:00
